The brand-new BMW 5 Series is officially listed at 439,900 yuan for sale.

Beijing News Shell Finance News (Reporter Wang Linlin) On January 25th, the Beijing News Shell Finance reporter learned from the official of BMW Group that the new BMW 5 Series was officially listed in the China market, and the new BMW 5 Series was launched with oil and electricity, namely the new BMW 5 Series long wheelbase version, the new BMW 5 Series standard wheelbase version, the innovative pure electric BMW i5 long wheelbase version and the innovative pure electric BMW i5. At the same time, the new BMW 5 Series offers luxury and M sports suits, and a total of 12 models are released. The official guide price is 439,900-639,900 yuan.

BMW i5。 Figure/car company official website

Gao Xiang, President and CEO of BMW Group Greater China, said that with the listing of BMW i5, the number of pure electric products provided by BMW brand to customers in China has increased to seven, and the pure electric products of BMW Group cover almost all major market segments. It is reported that the BMW i5 is equipped with the fifth-generation BMW eDrive electric drive system.

In addition, the new BMW 5 Series long wheelbase, which is specially built for the China market, not only lengthens the wheelbase, but also adds unique styling and color matching, exclusive equipment and localized digital applications, and introduces the WeChat car version. In addition, the BMW Group said that the new BMW 5 Series long wheelbase version has the technical ability to expand to L3 automatic driving.

Editor Xu Chao

Proofread yang xuli

The Basic Contents and Features of General Specification Chinese Character List

  In order to better implement the Law of People’s Republic of China (PRC) on the National Common Language and Characters, promote the standardization of the national common language and characters, adapt to the actual needs of modern language life and the development of national informatization under the new situation, and provide the standards for the quantity, grade and font of Chinese characters commonly used in modern society, the Ministry of Education and the State Language Committee have organized and developed the List of Chinese Characters for General Standardization (hereinafter referred to as the List).


  First, the basic content of the word list


  A total of 8105 standardized Chinese characters are included in the Character List, which is divided into three levels according to the degree and scope of universality. Among them, the first-level word list is 3500 words, which is the most frequently used set of commonly used words, and its function is equivalent to the modern Chinese common word list, which mainly meets the needs of basic education and cultural popularization. The second-level word list consists of 3000 words, which together with the first-level word list constitutes a common word set in the general social application field, and its function is equivalent to the modern Chinese common word list, which mainly meets the general needs of using words in modern society. There are 1605 words in the third-level word list, which are not included in the first-level and second-level word lists of surnames, names, scientific and technical terms and classical Chinese characters in Chinese textbooks for primary and secondary schools, but are more common in specific fields, mainly taking care of the basic needs of the public for words in special fields.


  In order to clearly standardize the correspondence between Chinese characters and their corresponding traditional characters and variants, the Ministry of Education and the State Language Commission have also organized and developed the Comparison Table of Standardized Characters and Traditional Characters and Variants (hereinafter referred to as the Comparison Table), which is used as a supplementary table and the Character List. The Comparison Table lists the traditional characters and variant characters corresponding to 2,546 standardized Chinese characters, including 2,574 traditional characters and 1,023 variant characters.


  The collation of the correspondence between simplified characters and traditional characters in the Comparison Table is based on the Summary of Simplified Characters, and its overall spirit is consistent with that in the Summary of Simplified Characters. With the basic principle of not restoring traditional characters, 96 groups of simplified characters and traditional characters which can not be one-to-one correspondence are mainly decomposed. For example, the word "Dou [Dou]" in the Summary of Simplified Chinese Characters seems to have a one-to-one correspondence on the surface. In fact, in the text printed with traditional Chinese characters, the simplified word "Dou" corresponds to the word "Dou" and "Dou" respectively. The former means measuring instrument, with the sound d ǒ u; The latter means fighting, and the sound is du u. If it is not decomposed, it is possible to convert all the "dou" into "dou" in the conversion from simple to complex, so there will be errors such as "Big Dipper". The collation of the correspondence between simplicity and complexity in the Comparison Table provides convenience for the reading of ancient books and the exchanges between the three places.


  The collation of the correspondence between standard characters and variant characters in the Comparison Table is based on the first batch of variant characters collation table. In view of the complexity of variant forms and the numerous problems involved, the Comparison Table does not expand the scope of variant forms, but focuses on the revision of the original variant forms in the First Batch of Variant Forms. According to the actual needs of using Chinese characters in modern society, the Word List and the Comparison Table restore or partially restore some "variant characters" that still have great application value and are closely related to people’s daily life into standardized characters for the convenience of people. For example, the word "Pan" was abolished as a variant of "Pan" in the First List of Variant Characters, but "Pan" was originally a surname, which originated from Pan-Guo in the Zhou Dynasty and has a very long history. A surname character represents the blood of a family. Out of respect for the family tradition, the Character List restored this kind of Chinese characters to the third-level character list as a surname character. Another example is the word "Zhe". The First List of Variant Characters is regarded as a variant of "Zhe". However, after investigation, it is found that the word "Zhe" contains two auspicious characters, which looks auspicious. Tens of thousands of people across the country have chosen this word for their names. Taking into account the people’s demand for Chinese characters and the reality of Chinese characters, the Word List has included it in the three-level word list, which is specially used for Chinese characters for names. On the basis of the First List of Variant Characters, 26 words such as "frustration, withering and gouging out" are recognized as standard words in the Word List and the Comparison Table, and 45 words such as "shua, pan and zhe" are regarded as standard words in a specific sense.And in the "word list" or "comparison table" in the corresponding position to explain its scope of use.


  In terms of glyphs, the characters included in the List of Printed General Chinese Characters and the List of Modern Chinese General Characters are recorded according to the glyphs in the two lists. Words outside the two tables shall be uniformly adjusted according to the font rules inside the two tables.


  Second, the overall characteristics of the word list


  Under the guidance of the new concept of Chinese character standardization, the Word List was developed by using modern technical means according to the situation of Chinese characters in contemporary society and the needs of the information age. Compared with the past Chinese character standardization, the Word List mainly has the following characteristics:


  1. Set a number of specifications for the convenience of the public.


  Since the founding of New China, the state has attached great importance to the work of language and writing, and has done a lot of work in the collation and standardization of Chinese characters, and has successively published a variety of word lists, which has played an important role in standardizing the use of Chinese characters in society. However, because these specifications are independent and scattered, they are extremely inconvenient to use. To understand the correspondence between simplified Chinese characters and traditional Chinese characters, it is necessary to look up the Summary of Simplified Chinese Characters published by the China Language Reform Commission in 1964 (individual adjustments were made when the State Language Commission approved its re-publication in the State Council in 1986); To understand the corresponding relationship between standard characters and variant characters, we need to look up the First Batch of Variant Characters Arrangement Table jointly issued by the Ministry of Culture and the China Language Reform Commission in 1955. To understand the font standard, we need to look up the Font Table for Printing General Chinese Characters issued by the China Character Reform Commission in 1965. To understand the standard of character quantity, we need to look up the List of Common Characters in Modern Chinese and the List of Common Characters in Modern Chinese jointly issued by the State Language Committee and the State Press and Publication Administration in 1988. The development of "Character List" comprehensively integrates these independent Chinese character specifications, and covers the functions of various previous character lists with a character list and an annex, which greatly facilitates the use of the public.


  2. Eliminate the original differences and unify the norms and standards.


  Because the previous Chinese character specifications were formulated in different periods, for different situations and for different purposes, there was a lack of care between them, which inevitably led to contradictions. For example, the word "Bing" is treated as the variant of "Bing" in the First Batch of Variant Character Arrangement Table, and the Font Table of Printing General Chinese Characters is included as a standard character. The word "shame" is treated as the variant of "Yang" in the First List of Variant Characters; The Summary of Simplified Chinese Characters is simplified as "Hua" and regarded as a standard word. For these inconsistencies, users are often at a loss. This time, the development of the Word List has made key adjustments to these problems, given clear and unified norms and standards, and eliminated the original differences.


  3. Use modern means to select words scientifically and quantitatively.


  It has been more than 20 years since the previous specifications and standards were released at the latest. At that time, neither the development basis nor the development means could be compared with the present. For example, in the aspect of corpus foundation, the List of Common Words in Modern Chinese and the List of Common Words in Modern Chinese published in 1988 are based on 14 static word lists without frequency of use and 6 dynamic word lists with frequency of use. The largest number of these word lists is 7,754, and the smallest number is only 1,000, which is extremely uneven. The word list obtained by second-degree statistics of 20 word lists with different uses lacks objective and unified criteria for word selection, and the results obtained are bound to have certain limitations. The background of the development of "Character List" is very different from the past. Modern information technology provides a scientific means for the construction and application of large-scale corpora, while a large-scale and balanced corpus provides a reliable basis for the survey of Chinese characters’ traffic. The basic corpus used this time is the "Modern Chinese Balanced Corpus" of the State Language Commission, which is randomly sampled from a large number of corpora, with a total database of about 91 million characters, covering the corpus of nearly a century since the popularization of modern vernacular Chinese, covering 55 disciplines in content and having a very comprehensive corpus source. The size and balance of the corpus ensure the reliability of word frequency and coverage statistics. Coupled with the use of multiple auxiliary corpora, scientific statistical methods and reasonable manual intervention, it provides a strong guarantee for the scientific quantification and word selection of the Word List.


  4. Considering different needs, reasonable classification.


  The previous Chinese character norms were formulated in the era of cultural and educational popularization, and more attention was paid to the demand for Chinese characters at the popularization level. Nowadays, people’s cultural knowledge structure is increasingly diversified, and the social language life is increasingly diversified. As a national standard, Character List will face users from all walks of life in China. Different levels of education, different communication ranges and different industry demands will inevitably lead to different requirements for the use of Chinese characters. The Word List fully considers this point, and divides the received words into three levels according to the general degree and general scope, which reflects the demand differences of different classes and industries and reflects the actual use of modern Chinese characters, thus greatly improving the practicality of the Word List.


  5. Take care of people’s lives and include special words.


  The establishment of three-level word list is a highlight of Word List. In the past, the standardization of Chinese characters was limited to the general social application level, but with the development of society, the amount of Chinese characters used in society has gradually increased, and the use of Chinese characters in some special fields has become more and more close to people’s daily life, which has become an indispensable word for modern information storage and information transmission. Without standardizing these Chinese characters, people’s daily needs for Chinese characters cannot be met. Based on the principle of people-oriented, the "Character List" was formulated this time, and the Chinese characters in special fields closely related to people’s daily life were also included in the scope of Chinese character standardization. With reference to the information provided by the Ministry of Public Security, the Ministry of Civil Affairs, the Committee on Science and Technology Terminology and other relevant departments, the commonly used Chinese characters for surnames and names, Chinese characters for place names above the township level, Chinese characters for science and technology related to people’s lives, and Chinese characters for printing teaching materials are specially collected to form a three-level character list, thus solving the problem of Chinese characters for surnames and names such as ID cards and household registration cards to a certain extent, and meeting the needs of people for Chinese characters in special fields such as medicine and nutrition in their daily lives.


  In addition, the development of the Word List has attracted widespread attention from all walks of life, and all major departments and fields have given strong support and help. A large number of experts and scholars have directly or indirectly participated in the development work, and the general public has also expressed their personal opinions and suggestions in various ways. This practice of developing norms and standards nationwide and socialized is also a major feature of the Word List that is different from the past. (Wang Lijun, male, professor and doctoral supervisor of the School of Literature, Beijing Normal University, director of the Chinese Character Research Office of the Folk Classics Research Center of the Key Research Base of Humanities and Social Sciences of the Ministry of Education, and one of the "Outstanding Talents in the New Century" of the Ministry of Education. )

The ability of monitoring and early warning of severe weather will be further improved.

Beijing, 10 Jan (Xinhua) reporter Chen Haibo learned from the National Meteorological Work Conference on the 10th that in 2024, China will further improve its ability of monitoring and early warning of severe weather and do its best to prevent and reduce meteorological disasters.

Chen Zhenlin, director of China Meteorological Bureau, introduced at the meeting that in 2023, China’s meteorological science and technology business capacity will be steadily improved. The forecast error of typhoon’s 24-hour average path is 62 kilometers, which is the best in history. The accuracy of 24-hour rainstorm forecast has reached a new high; The warning signal of severe convective weather was released 43 minutes in advance.

According to reports, the meteorological department should strengthen the risk prediction and response of meteorological disasters, pay close attention to monitoring, forecasting and early warning services, further improve the linkage mechanism of disaster prevention and mitigation led by meteorological early warning, build the first line of defense for meteorological disaster prevention and mitigation, and promote the whole society to effectively resist risks.

In 2024, the meteorological department will further improve the ability of monitoring and early warning of severe weather by strengthening the monitoring and early warning of short-term approaching weather, doing a good job of point-to-point accurate forecasting and rolling update, strengthening the construction of national and provincial short-term monitoring and early warning platforms, promoting the adjustment of rainstorm early warning signals, and piloting seamless climate impact prediction.

At the same time, the meteorological department will also improve the emergency response and linkage mechanism for disaster prevention and mitigation. In 2024, the meteorological department will promote the comprehensive integration of meteorological services into the local comprehensive disaster prevention and mitigation command and dispatch work system, improve the "calling" mechanism and process of high-level meteorological disaster early warning, fully implement the progressive meteorological service mechanism, encourage chief forecasters to interpret weather trends and disasters online, and enhance the prevention ability of meteorological disasters in the whole society.

In addition, this year, we will develop meteorological disaster risk prediction business, strengthen the research and development of risk prediction algorithms and scientific testing of single disaster, multi-disaster and disaster chain, establish and improve the national and provincial integrated meteorological disaster risk prediction business system, and strengthen the application of various products in meteorological disaster prevention decision-making. Improve the ability of weather modification and carry out experiments and demonstrations of key technologies.

Original title: The ability of monitoring and early warning of severe weather will be further improved.

(Source: Guangming Daily Editor: Yan Fei)

The 2025 Kia EV5 Guangzhou Auto Show was launched, with a price of 149,800, a new choice for pure electric SUVs.

On November 15, 2024, the 2025 Kia EV5 was officially launched, with a price of 149,800 yuan. Based on the special E-GMP platform for Kia electric vehicles, this household pure electric SUV is the first global strategic vehicle launched by Kia in China. In addition to the regular version, the GT-Line version was also launched, with a price of 214,800 yuan, equipped with front and rear dual motors, and the power performance was significantly improved.

Consumers who purchase the 2025 KIA EV5 can enjoy financial rights including 0 down payment, 0 interest for 3 years, and financial discount up to 23,000 yuan. The vehicle warranty period is 5 years or 100,000 kilometers, and the three-power warranty period is 8 years or 150,000 kilometers. In addition, there is an increase of 7,000 yuan. The special support of yueda Group includes free basic maintenance materials for five times in five years, cash subsidies or coupons of 5,000 yuan, and five years of free unlimited full data traffic and other maintenance and interconnection rights.

In appearance, the 2025 KIA EV5 continues the family-style design language of "Opposites United Unity of Opposites". The front face adopts a C-shaped LED headlight group, and the side lines of the car body are tough, equipped with hidden door handles and low wind resistance styling wheels. In the rear part, the taillights are simple in shape and similar in style to the headlights. The body size is 4615/1875/1715mm and the wheelbase is 2750mm. The EV5 GT-Line version is blackened in appearance and equipped with 20-inch wheels to enhance the sense of movement.

For the interior, KIA EV5 is equipped with a 12.3-inch full LCD instrument and a 12.3-inch multimedia screen, with the latest generation ccNC in-vehicle infotainment system built in, and the physical buttons and touch buttons are retained. In terms of power, the maximum power of the motor before and after the EV5 GT-Line version is 160kW and 73kW respectively, and the comprehensive maximum power of the system is 233kW. The maximum power of the motor of the regular model is 160kW, and the pure battery life of CLTC is 530km and 720km.

The 15th anniversary of China’s accession to the World Trade Organization has made the pace of its integration into the world firmer.

  On December 11th, 2016, it has been 15 years since China joined the World Trade Organization (WTO). In the historical process of China’s reform and opening up, China’s accession to the WTO is a key turning point. On December 11th, 15 years ago, China and the world took that important step together, which not only made China more closely connected with the world, but also made China more firmly integrated into the world.

  Mutual benefit and win-win, the biggest "gift package" brought to China and the world.

  In the 15 years since China’s entry into WTO, China has benefited from the development of globalization, and at the same time, it has been more deeply integrated into the world economy, becoming an indispensable and important force to promote the development of the world economy. Mutual benefit and win-win is an accurate description of the changes in the relationship between China and the world in the past 15 years.

  "Joining the WTO is an important milestone for China’s economy to integrate into the world economy, and it is also an objective need for China to adapt to the development trend of economic globalization and further deepen reform and opening up." Gu Xueming, president of the Institute of International Economic and Trade Cooperation of the Ministry of Commerce, pointed out in an interview with the Economic Daily that "joining the WTO has played an important role in promoting China’s foreign trade development and stimulating economic growth."

  Gu Xueming pointed out that, for China, by joining the WTO, China began to participate in the multilateral trading system, and established closer cooperative relations with other countries in international trade, investment, service and technology transfer, which in turn helped China to use factors and markets in a wider range, pushed reform and opening up to a new stage, and greatly promoted the development of social productive forces. At the same time, China’s accession to the World Trade Organization has enabled China to enjoy the results of tariff concessions in eight rounds of negotiations since the establishment of the General Agreement on Tariffs and Trade, and enjoy the GSP treatment more widely, greatly improving China’s terms of trade, and at the same time promoting China’s further reform of its foreign economic and trade system, and taking important steps.

  On the whole, from 2002 to 2015, the real GDP of China achieved an average annual growth rate of 9.74%. In 2001, China’s GDP was US$ 1.33 trillion, accounting for only 4.02% of the global GDP. By 2015, China’s GDP will reach US$ 10.87 trillion, accounting for 14.78% of the world’s total, ranking second in the world, up by 10.76 percentage points compared with that before China’s entry into WTO. According to the trade data, from 2002 to 2015, the import and export of China achieved an average annual growth rate of 15.31%. In 2001, China’s total import and export volume was 0.51 trillion US dollars, accounting for only 4.02% of the global import and export volume. After 15 years, in 2015, China’s total import and export volume was 3.96 trillion US dollars, about 8 times of the total import and export volume before China’s entry into WTO (2001), accounting for 11.89% of the global import and export volume, which was 7.87 percentage points higher than that before China’s entry into WTO.

  "Since China’s accession to the WTO, it has made efforts to reform its domestic economic system and legal system in accordance with WTO rules, which has enabled China to integrate into the global economic system more quickly, and its foreign economic and trade activities have increased rapidly, and its share of trade and investment in the world has also increased substantially, effectively boosting China’s economic growth." Professor Sang Baichuan, dean of the Institute of International Economics of the University of International Business and Economics, said in an interview with the Economic Daily that China’s accession has also provided more trade and investment opportunities for other WTO members, which has boosted the growth of the world economy. "In the past 15 years, China has contributed the most to the growth of world economy and trade among the members of the World Trade Organization."

  Over the past 15 years, China’s contribution rate and pull to world economic growth have been continuously improved. From 2002 to 2015, the proportion of China’s GDP in the world increased from 4.25% to 14.78%. If we look at the two points before and after China’s entry into WTO, we can find that in 2001, before the entry into WTO, the contribution rate of China’s real GDP to the world was only 0.53%, and the pulling degree to the global real GDP growth rate was 0.03 percentage points. However, by 2015, the contribution rate of China’s real GDP to the world is 24.8%, and the driving force to the global real GDP growth rate is 0.6 percentage points.

  "In a global sense, China’s entry into WTO has injected new vitality into the further development of economic globalization", Gu Xueming pointed out, "China has driven the development of the world economy with its own development".

  Keeping its promise, China constantly promotes the improvement of international trade rules.

  In the past 15 years, the changes brought about by China’s accession to the WTO are not only reflected in its strong support for the world economy, but also in its commitment to the WTO, its respect for WTO rules and its promotion of the development of international trade rules in a more just and reasonable direction. As a representative of emerging economies, China has promoted the change of irrational and unjust international economic order and the evolution of global economic governance.

  "The integration of China and the world economic system is not only reflected in the integration of capital, resources and markets, but more importantly, the docking of rules." Researcher Xing Houyuan, deputy director of the China Service Outsourcing Research Center, pointed out in an interview with this reporter that in the past 15 years, China’s compliance with WTO rules has made great contributions. "Multilateral rules have been practiced and promoted in China, the world’s most populous market and the second largest economy in the world."

  After China’s entry into WTO, China has become an active participant, defender and contributor to the multilateral trading system, and advocates that the multilateral trading system represented by WTO should be the main channel of global trade rules. Over the past 15 years, China has taken practical actions to safeguard the multilateral trading system, participated in the construction of the multilateral trading system in an all-round way, and continuously improved its position and role in many WTO negotiations. China is committed to the progress of the Doha Development Round and actively participates in all rule-making and market opening negotiations within the WTO framework; Strictly implement the WTO ruling, use the trade dispute settlement mechanism to oppose trade protectionism, and file 13 lawsuits with the WTO; Successfully passed six WTO trade policy deliberations; Support the least developed countries and developing countries, and from December 10, 2015, implement zero tariffs on 97% of the tax items of 33 least developed countries that have established diplomatic relations and completed the exchange of letters; As the host country of the Asia-Pacific Economic Cooperation (APEC) meeting in 2014 and the presidency of the G-20 in 2016, we have sent a positive signal together with all parties to support the multilateral trading system and resolutely oppose protectionism.

  At the beginning of China’s entry into WTO, the tariff level was greatly reduced at first, and the tariff levels of industrial products and agricultural products were lowered to varying degrees. China has been working hard to promote the implementation of trade facilitation and investment facilitation. In terms of market access for service trade, China has continuously expanded the scope of market access for service trade. In terms of investment access, China has introduced the market access mode of national treatment plus negative list. In addition, bold efforts have been made to reduce non-tariff measures. At the same time, a large number of administrative examination and approval items have been cleared up, many administrative examination and approval contents have been cancelled, and a series of international economic and trade laws and regulations have been revised. China has made great improvements in intellectual property protection, environmental standards, import and export inspection and quarantine system, foreign exchange management system and international capital flow management system.

  "As a member of the World Trade Organization, China is not only trying to adapt to the requirements of the rules of the World Trade Organization, but also trying to carry out effective cooperation with developing and developed members to promote the improvement of the rules of the World Trade Organization," Sang Baichuan told reporters. For example, in the Doha Round negotiations, China was an active contributor. China also plays a constructive role in promoting fair trade and promoting negotiations on common issues of common concern. "China is an important builder of the World Trade Organization and an important force for adhering to the multilateral economic and trade system."

  "China has made efforts to promote the development of international trade rules in a more reasonable and just direction," Gu Xueming pointed out. On the one hand, China has fully participated in the construction of the multilateral trading system, and its position and role in many WTO negotiations have been continuously improved. China promoted the conclusion of the WTO Agreement on Trade Facilitation and the Agreement on Information Technology (ITA), and contributed to its early implementation. At present, China is actively participating in a number of plurilateral negotiations under the WTO framework, including participating in the negotiation of the Agreement on Environmental Products as a sponsor, submitting six bidding lists for China’s accession to the Agreement on Government Procurement to the WTO, and applying to join the negotiation of the Agreement on Trade in Services. On the other hand, China is committed to building a high-level free trade zone. Up to now, 14 free trade agreements have been signed and implemented, involving 22 countries and regions. China-South Korea and China-Australia Free Trade Zones cover new issues such as intellectual property rights, competition, cross-border e-commerce and environment, while China-US and China-EU new generation investment agreements and RCEP negotiations pay more attention to investment liberalization, and adopt the mode of pre-entry national treatment plus negative list. In November 2016, China and New Zealand initiated negotiations on upgrading the China-Singapore FTA.

  Open wider to the outside world, persist in economic globalization and oppose protectionism.

  The changes and adjustments brought about by the international financial crisis are still going on, and the economic and trade pattern including world trade, investment and industrial chain is also undergoing profound changes. What kind of strategy China will adopt in the future to face the development and changes of global trade pattern and multilateral trading system is a question worthy of serious consideration.

  The current multilateral trading system has made remarkable achievements since its establishment in 1995. The total trade volume of more than 160 member countries accounts for more than 90% of global trade, which has played an irreplaceable role in global trade and investment liberalization and world economic growth. However, the existing international trade rules, based on traditional trade issues, are mainly used to regulate the cross-border trade flow of goods, which has fallen far behind the actual needs. At present, trade protectionism is on the rise, trade friction is intensifying and the international trade environment is deteriorating, which hinders the recovery of the world economy. Therefore, China is actively seeking ways to promote the upgrading of multilateral trade rules, promote the negotiation of WTO plurilateral agreements, and support the early completion of the Doha Round of WTO negotiations.

  "In the future, China should continue to oppose trade protectionism, strengthen international cooperation and jointly safeguard the multilateral trading system. Give full play to the important role of the dispute settlement mechanism under the WTO framework in maintaining the stability and predictability of the multilateral trading system, "Gu Xueming told reporters:" WTO members will not easily give up the multilateral trading system that benefits the global economy, and China will continue to make efforts to support the early completion of the WTO Doha Round negotiations and truly realize the development goals set by all members. "

  "For the current trade protectionism, we should not only stay at the level of advocacy and moral accusation, but also take practical measures at the multilateral level, and the overall framework should be adjusted." Xing Houyuan said that only when the restraint mechanism is perfect and trade protectionism is actually restrained can we maintain the fair development of global trade.

  "Under the framework of the World Trade Organization, maintaining a fair and free trade system is the direction that China should stick to". Sang Baichuan pointed out that in the development of international economic and trade rules, the distribution of interests among WTO members is unbalanced. The income of different classes within a member is also uneven. Under the two unbalanced conditions, different views and strategies on trade liberalization have been triggered. Some WTO members have picked up the means of trade protection, which has also formed an impact on the multilateral system. In the future, China should promote the improvement of international economic and trade rules and reform the global economic governance system in accordance with the basic concepts of fairness, openness, sharing and mutual benefit. "We should give full play to the basic role of the WTO in global economic governance, take the multilateral system as the foundation and regional cooperation as the starting point, and jointly promote the liberalization and fairness of international economic and trade from both multilateral and regional dimensions."

Tesla’s market value evaporated over 960 billion yuan overnight.

On December 18th, the three major indexes of US stocks all fell sharply, and large-scale technology stocks fell across the board, among which Tesla fell more than 8%, and its market value evaporated by 131.5 billion US dollars (about 962.5 billion yuan) overnight.

In addition to Tesla, other large-scale technology stocks such as Intel, Amazon, Google, Microsoft, etc. also fell in succession, all of which fell by more than 2%: Intel fell by more than 5%, Amazon fell by more than 4%, Google, Meta, Microsoft and Netflix fell by more than 3%, Apple fell by more than 2%, and NVIDIA fell by more than 1%.

On December 18th, local time, the Federal Reserve announced that it would cut the target range of the federal funds interest rate by 25 basis points to between 4.25% and 4.50%, which was in line with the general market expectation. This is the third time that the Fed cut interest rates after cutting interest rates by 50 basis points in September and 25 basis points in November.

Federal Reserve Chairman Powell decided to hold a press conference on the same day to cut interest rates, releasing many policy signals. He said that the Fed should be "more cautious" when considering adjusting the policy interest rate in the future. Powell said that the decision to cut interest rates in December was more challenging, but it was the "right decision". He said that whether the Fed will cut interest rates in 2025 will be based on future data, not the current forecast results, and the Fed will consider further interest rate cuts after inflation improves.

Powell also said that the Fed is at or near the time of slowing down interest rate cuts. The three major indexes of US stocks fell sharply on the same day, and the Nasdaq fell by 3.56%, the biggest one-day drop since July 25th. The S&P 500 index fell 2.95%, the biggest one-day drop since August 6; The Dow fell 2.58%, falling for the tenth consecutive day, the longest losing streak since October 1974.

(Yangcheng Evening News Yangcheng School Comprehensive CCTV News, The Paper, etc.)

Tengshi D9 car purchase manual sells at a price close to the people.

In the eyes of ordinary consumers, they still buy cars mainly to meet daily transportation, so they will pay more attention to practicality and practicality. What I bring to you today is that it has many highlights. Come and see it quickly.

First of all, from the appearance, Tengshi D9 front gives people a very fashionable and dynamic feeling, and looks younger. Coupled with the headlights, it is full of simplicity. The car is equipped with LED daytime running lights, automatic opening and closing, adaptive far and near light, delayed closing, rain and fog mode and so on. Coming to the side of the car body, the size of the car body is 5250MM*1960MM*1900MM, and the car adopts soft lines, which gives people a very beautiful feeling. With large-sized thick-walled tires, the shape is quite fashionable and sporty. In terms of the rear, Tengshi D9 has a simple rear line, and the taillights are very delicate and neat.

Sitting in the car, the interior looks very delicate, which is very in line with the tastes of young consumers. The car looks very good outside the steering wheel. It is equipped with the functions of manual steering wheel up and down+front and rear adjustment, steering wheel heating and so on, which gives people a bright feeling. From the central control point of view, with the 15.6-inch central control screen, the interior style is impressive and meets the aesthetic standards of most consumers. Let’s take a look at the dashboard and seats again. It looks like a strong sense of technology. The car adopts leather seats, equipped with functions such as electric adjustment of auxiliary seats and electric adjustment of seats with memory, which further improves the comfort of drivers and passengers.

The car is equipped with car networking, driving mode selection, remote control key, Bluetooth key, NFC/RFID key, UWB digital key, rear wiper, interior atmosphere light and other configurations, which greatly improves the convenience of using the car.

After reading the above description, Xiaobian will make a summary. The car introduced today is remarkable in terms of space, configuration and power, and home travel is also a good helper.

Technology giants "cross-border" to fight cancer

  Cancer can be described as the sword of Damocles hanging on everyone’s head. How to cure cancer is one of the most important topics in the field of science at present, and it has also attracted the attention of many scientists, including the technological giants who have always been "trendsetters" of the times.

  Although Microsoft, Google, IBM and other companies are famous for their software, computers or mobile phones, now they have begun to devote themselves to the war against cancer without smoke, hoping to cure cancer as soon as possible. Microsoft even said that the latest method it developed may eradicate cancer within 10 years.

  Microsoft: Fighting Cancer with Cell Programming

  Microsoft Research Lab is located in Cambridge University, England. It has attracted many of the best biologists, programmers and engineers in the world. These 150 professionals are working on many projects as part of the "Biocomputing" unit. Their ultimate goal is to deal with cancer.

  According to a recent report by the British Daily Mail, scientists in this laboratory regard cancer as a big loophole in the computer system. They hope to make cells into living computers within 10 years, and then treat diseases including cancer by programming and reprogramming these cells.

  Chris Bishop, the head of the laboratory, said in an interview with Fast Company magazine: "The fields of biology and computing seem to be irrelevant; But in fact, the complex processes that occur in cells are very similar to those that occur in computer systems. "

  Zhou Yizhen, Microsoft’s global senior vice president in charge of the research laboratory, explained that Microsoft’s solution to cancer is based on two basic methods: First, cancer and other biological processes are information processing systems, and the laboratory of Cambridge University is currently conducting research based on this idea; Second, researchers can apply technologies such as machine learning to biological data. Therefore, "collaboration between biologists and computer scientists is crucial".

  In 2012, researchers at Stanford University in the United States made a complete computer model of organic matter for the first time. The bacterial model of Mycoplasma genitalium was based on the data extracted from 900 scientific papers, and its performance was almost exactly the same as that of real bacteria. Since then, the field of computational biology has developed.

  Simulating life enables scientists to carry out more complex experiments. At present, Microsoft’s programming team has developed software that can simulate the healthy behavior of a cell. Next, scientists will start to write code, so that healthy cells can be compared with sick cells to learn where the problem lies and how to solve it.

  In the short term, the computational model developed by Microsoft scientists can help pharmaceutical companies to develop new drugs. Andrew Phillips, head of the research team, said: "In the long run, it is technically feasible to propose an intelligent molecular system that can detect diseases within 5 to 10 years."

  James Fisher, a senior researcher at Microsoft and an associate professor at Cambridge University, told the Daily Telegraph: "If we can control and manage cancer, it will probably become similar to a chronic disease, and the problem will be solved. I believe that in the next 10 years, we will be able to completely eradicate cancer. "

  IBM: Using Artificial Intelligence to Deal with Cancer

  Unlike Microsoft, which regards cancer cells as loopholes in computer systems, IBM’s magic weapon against cancer is its Watson artificial intelligence system.

  According to a recent report in the Nihon Keizai Shimbun, IBM and the Institute of Medical Science of the University of Tokyo will jointly develop a method to treat cancer with Watson. IBM will input the latest data of papers and drug efficacy in Japan and abroad into Watson; Scientists in the institute will input genetic data extracted from the blood and tissues of Japanese cancer patients. According to the database, "Watson" will be able to propose a treatment plan suitable for patients such as drugs with less side effects and better efficacy in about 10 minutes.

  It is reported that they used this method to judge that a 60-year-old woman has rare leukemia, and proposed a treatment plan to the researchers, which made an important contribution to the rehabilitation of this woman.

  In fact, "Watson" has already entered the field of cancer treatment. In May last year, IBM announced that 14 cancer centers from the United States and Canada would deploy the "Watson" computer system to select the appropriate treatment plan according to patients’ tumor genes.

  According to MIT’s Technology Review, Watson has learned 600,000 medical evidence reports and 150 patients’ case and clinical trial reports, which can help doctors design more accurate cancer treatment programs for patients.

  Google: Using Intelligent Algorithms to Accurately Fight Cancer

  Google has taken a different approach and developed algorithms to deal with cancer.

  MIT Technology Review magazine reported that Google’s machine learning division "DeepMind" plans to use artificial intelligence algorithms to streamline complex cancer radiotherapy programs, hoping to shorten the treatment time, thus greatly reducing the burden on doctors and the pain of patients.

  "Deep Thinking" will cooperate with University College London Hospital to analyze the scanned images of 700 patients who have suffered from head and neck cancer, create an algorithm to learn how doctors make decisions during radiotherapy, and finally realize automatic "segmentation" scanning to reduce the burden on doctors. "Segmentation" refers to the process that doctors need to manually draw the radiotherapy area when giving radiotherapy to cancer patients, find out the correct position of X-ray scanning to kill tumor cells and minimize the damage to surrounding healthy tissues.

  However, the company explained that it is still up to clinicians to decide whether to reduce the radiotherapy procedure in the end, but they hope to reduce the "segmentation" process from 4 hours to about 1 hour. In addition, this algorithm can also be used for the treatment of other cancers.

  Although the above companies have different methods, they all reach the same goal, and the ultimate goal is to remove the "cancer" in the history of human civilization — — Cancer.

  (Science and Technology Daily, Beijing, October 10th)

Take you to a comprehensive understanding of mRNA vaccine

Source | Xiao Yao Shuo Yao
vaccine
It is the most effective public health intervention measure to prevent the spread of infectious diseases. Successful vaccination has eradicated many life-threatening diseases, such as smallpox and polio. The World Health Organization estimates that vaccines can prevent 2-3 million people from dying of tetanus, whooping cough, influenza and measles every year. However, despite the obvious success of conventional vaccines, they can not effectively deal with pathogens such as plasmodium, hepatitis C and HIV that escape immune surveillance. In addition, they need to be modified regularly to cope with rapidly changing pathogens, such as influenza virus.
on the basis ofmRNAOur nucleic acid vaccine was put forward more than 30 years ago, hoping to produce a safe, multifunctional and easy-to-produce vaccine. Compared with traditional vaccines, mRNA vaccines have many advantages: Unlike some viral vaccines, mRNA will not be integrated into the genome, thus avoiding the concern about insertion mutation; MRNA vaccine can be made in a cell-free way, so as to realize rapid, economical and efficient production. In addition, a single mRNA vaccine can encode multiple antigens, enhance the immune response against adaptive pathogens, and can target multiple microorganisms or virus variants with a single formula.
At first, mRNA therapy was not paid attention to because of concerns about its stability, inefficiency and excessive immune stimulation. However, in the past decade, the field of mRNA therapy has changed with each passing day, including the in-depth study of mRNA pharmacology, the development of effective vectors and the control of mRNA immunogenicity, which has made the clinical application of mRNA vaccine enter a brand-new stage.
Design and synthesis of mRNA
In vitro transcription (
IVT
) mRNA mimics the structure of endogenous mRNA and has five parts, from 5 to 3, including: 5?cap, 5 untranslated regions (
UTR
), an open reading frame encoding antigen, 3?UTR and a PolyA tail.
Like natural eukaryotic mRNAs, the 5′ end cap structure contains a 7- methylguanosine nucleoside, which will protect mRNA from being degraded by nucleic acid exonuclease in space, and cooperate with translation initiation factor protein to recruit ribosomes to start translation. The length of PolyA tail indirectly regulates mRNA translation and half-life.
5 ′ and 3 ′ UTR on both sides of the coding region regulate mRNA translation, half-life and subcellular localization, and are derived from highly expressed genes (
Such as alpha-and beta-globin genes.
) is the first choice for synthesizing mRNAs. In addition, UTR can be optimized according to the cell type, for example, by removing miRNA binding sites and AU-rich regions in 3 ′ UTR, the degradation of mRNA can be minimized.
The open reading frame of mRNA vaccine is the most critical component. Although the open reading frame is not as plastic as the non-coding region, the translation can be increased without changing the protein sequence by optimizing the codon. For example, CureVac AG found that human mRNA codons rarely have A or U in the third position, thus replacing A or U in the third position of the open reading frame with G or C.. This optimization strategy is applied to its SARS-CoV-2 vaccine CVnCoV, which is currently in the phase III trial stage.
In order to maximize translation, mRNA sequences usually contain modified nucleosides, such as pseudouridine, N1- methyl pseudouridine or other nucleoside analogues. The use of modified nucleosides, especially modified uridine, prevents the recognition of pattern recognition receptors and ensures that the translation process produces a sufficient level of protein. Both Moderna and Pfizer–Biontech SARS-CoV-2 vaccines contain nucleoside modifications. Another strategy to avoid pattern recognition receptor detection, pioneered by CureVac, uses sequence engineering and codon optimization to consume uridine by increasing GC content of vaccine mRNA.
Besides the improvement of mRNA sequence, great progress has been made in simplifying mRNA production. The synthetic mRNA used in clinic is synthesized by using phage RNA polymerase T7 (
T3 and SP6 polymerases can also be used.
) transcribed from DNA plasmid in vitro. In addition, the co-transcription capping technology of CleanCap is used to simplify the purification steps.
Vector of mRNA vaccine
Due to the large mRNA (
10four–10sixDa
) and is negatively charged, so it cannot pass through the anionic lipid bilayer of the cell membrane. In addition, in vivo, it will be swallowed by cells of innate immune system and degraded by nuclease. Therefore, in vivo application requires the use of mRNA delivery vectors, which transfect immune cells without causing toxicity or unnecessary immunogenicity. At present, many solutions based on innovative materials have been developed.
Lipid nanoparticles (LNP)
Lipid nanoparticles are the most advanced mRNA carriers in clinic. As of June 2021, all SARS-CoV-2 mRNA vaccines being developed or approved for clinical use have adopted LNPs. LNP provides many benefits for mRNA delivery, including simple preparation, modularization, biocompatibility and large mRNA payload capacity. In addition to RNA drugs, LNP usually consists of four components: ionizable lipid, cholesterol, accessory phospholipid and polyethylene glycol lipid, which together encapsulate and protect fragile mRNA.
Ionizable lipid and mRNA form nanoparticles in acidic buffer, which makes lipid positively charged and attracts RNA. In addition, they are positively charged in the acidic environment of endosome, which promotes their fusion with endosome membrane and releases them into cytoplasm.
DODAP and DODMA are the first ionizable lipids for RNA delivery. Through the design to improve the efficiency of DODMA, DLin-MC3-DMA was produced. This is the first ionizing lipid used in FDA-approved pharmaceutical preparations: siRNA drug patisiran (
Onpattro
)。 In addition to the effective and safe delivery of siRNA, DLin-MC3-DMA is also used for the delivery of mRNA.
At present, many groups in academia and industry use combinatorial reaction schemes to synthesize potential delivery materials. This method produces many effective lipids, including C12-200, 503O13, 306Oi10, OF-02, TT3, 5A2-SC8, SM-102 (
Moderna vaccine mRNA-1273 for anti-SARS-CoV-2
) and ALC-0315 (
BNT162b2 for Pfizer vaccine
)。
In addition to seeking to improve the curative effect, people pay more and more attention to improving the specificity of drugs, especially for vaccines and immunotherapy. Lipid 11-A-M58 containing polycyclic adamantane tail and lipid 93-O17S59 containing cyclic imidazole head have been designed to target T cells in vivo. Although the mechanism is not clear, the cyclic groups of these lipids are essential for targeting T cells.
Although ionized lipid can be said to be the most important component of LNP, the other three lipid components (
Cholesterol, auxiliary lipids and polyglycolized lipids
) also promoted the formation and function of nanoparticles. Cholesterol is a naturally occurring lipid, which enhances the stability of nanoparticles by filling the gaps between lipids, and helps to fuse with endosomal membranes during uptake into cells.
Auxiliary lipid can adjust the fluidity of nanoparticles and enhance the efficacy by promoting the lipid phase transition which is helpful to the fusion of membrane and inclusion body. The choice of the best auxiliary lipid depends on the ionizable lipid material and RNA vector. For example, for lipid-like materials, saturated auxiliary lipids (
Such as DSPC
) is most suitable for delivering short RNA (
Such as siRNA
), while unsaturated lipids (
Such as DOPE
) is most suitable for delivering mRNA. DSPC has been used in the SARS-CoV-2 vaccines mRNA-1273 and BNT162b2 approved by FDA.
The PEGylated lipid component of LNPs consists of polyethylene glycol (
PEG
) and anchored lipids (
Such as DMPE or DMG
) combined. Hydrophilic PEG can stabilize LNP, adjust the size of nanoparticles by limiting lipid fusion, and increase the half-life of nanoparticles by reducing nonspecific interaction with macrophages. Both mRNA-1273 and BNT162b2 SARS-CoV-2 vaccines contain PEGylated lipids.
Polymers and polymer nanoparticles
Although the clinical progress is not as good as LNP, polymers have similar advantages to lipids and can effectively deliver mRNA. Cationic polymers concentrate nucleic acids into complexes with different shapes and sizes, which can enter cells through endocytosis.
Polyethylenimine is the most widely studied nucleic acid delivery polymer. Although its efficacy is excellent, its toxicity limits its application because of its high charge density. In addition, several biodegradable polymers with less toxicity have been developed. For example, poly (
β-amino ester
) is excellent in mRNA transmission, especially for lung.
Recently, a new type of lipid-containing polymer, called charge-changing releasable transporter (
CARTs
), it can effectively target T cells, and it is very difficult to manipulate T cells. Therefore, CART is an attractive delivery material with great potential in the fields of mRNA vaccine and gene therapy.
Other delivery systems
In addition to lipids and polymer carriers, peptides can also deliver mRNA to cells, thanks to cations or amphiphilic amine groups in their main and side chains (
Such as arginine
), these cations or amphiphilic amino groups electrostatically combine with mRNA and form nanocomposites. For example, amino acids containing repeated arginine-alanine-leucine-alanine (
RALA
) motif of membrane fusion cell penetrating peptide.
Protamine peptide rich in arginine is positively charged at neutral pH, which can also concentrate mRNA and promote its transmission. Protamine-mRNA complexes activate Toll-like receptors that recognize single-stranded mRNA (
TLR7,TLR8
) pathway, therefore, it can also be used as an adjuvant for vaccine or immunotherapy applications. CureVac AG is evaluating a protamine-containing delivery platform RNActive for clinical trials of melanoma, prostate cancer and non-small cell lung cancer.
Finally, cationic nanoemulsions based on squalene can also deliver mRNA, and these nanoemulsions are composed of oily squalene cores. Some squalene preparations, such as Novartis MF59, are used as adjuvants in FDA-approved influenza vaccines. MF59 makes the cells at the injection site secrete chemokines, thereby recruiting antigen presenting cells, inducing monocytes to differentiate into dendritic cells, and enhancing antigen uptake by antigen presenting cells. The mechanism of squalene-based cationic nanoemulsion escaping from endosome and transporting mRNA to cytoplasm is not clear.
Technical innovation of mRNA vaccine
The most important innovations of mRNA vaccine technology are: mRNA sequence design; Develop a simple, rapid and large-scale method to produce mRNA; To develop efficient and safe mRNA vaccine delivery materials.
A recent study used a systematic selection process based on cell culture to identify new UTRs, which significantly increased the protein expression of IVT mRNA. Compared with human β -globin 3’UTR, these sequences can induce the protein of related transcripts to be about 3 times.
In addition, an interesting new vaccine form was recently reported, which used mRNA encoding RNA-dependent RNA polymerase of α virus plus a second mRNA encoding antigen to make it replicate in cytoplasm. This system can be used at very low doses (
50ng
) can effectively induce protective immune response in mice. These findings are particularly attractive because the use of low doses reduces the cost of vaccine production. No delivery material further reduces the cost, simplifies the manufacture, and improves the possibility of freeze-drying and storage of vaccines at ambient temperature.
On the production side, in addition to the cleancap technology, a method for adsorbing double-stranded RNA pollutants to cellulose (
A cheap and abundant polysaccharide
) to purify mRNA. It has been proved that this highly scalable and cheap method is as effective as high performance liquid chromatography in removing dsRNA pollutants from IVT mRNA samples.
In terms of delivery materials, mRNA-LNPs also achieves selective T cell targeting, similar to CAR-T platform based on polymer. A new platform called ASSET (
Anchored secondary targeting single chain antibody
), in which T cell-specific monoclonal antibodies are linked to LNP to target T cells. This flexible platform also has great potential in mRNA vaccine and other applications.
Another lipid complex preferentially targets dendritic cells after systemic administration. It is a potential key discovery to selectively target DC with mRNA vaccine to induce strong immune response, and the platform has proved its prospect in clinical trials.
Research progress of mRNA vaccine in infectious diseases
MRNA-based therapy represents a relatively novel and efficient drug class. Recently, several published studies have emphasized the potential efficacy of mRNA vaccine in the treatment of different types of malignant tumors and infectious diseases, in which traditional vaccine strategies cannot cause protective immune response.
By the end of 2019, 15 candidate mRNA vaccines against infectious diseases had entered clinical trials. At that time, it was thought that it would take at least 5-6 years for mRNA vaccines to be approved by the regulatory authorities. However, when COVID-19 pandemic swept the world in early 2020, these expectations were subverted. In the next few months, the research, development, manufacture and deployment of mRNA vaccine have entered a stage of rapid leap.
SARS-CoV-2 vaccine
Most candidate vaccines of SARS-CoV-2 have an immune response to spinous proteins on the virus surface. Spike protein binds to the receptor angiotensin converting enzyme 2 on the surface of its host cell. Then, the cell’s transmembrane serine protease 2 cleaves the attached spike protein, which induces conformational changes, exposes the fusion peptide of spike protein and promotes the fusion with the cell or endosomal membrane. Usually, the antigen encoded by vaccine mRNA is either the full-length spike protein or the receptor binding domain of spike protein.
As of June 18th, 2021, 185 CVID-19 vaccine candidates are in the pre-clinical development stage, and another 102 have entered clinical trials. In clinical trials, 19 kinds are mRNA vaccines. On December 11th, 2020, Pfizer’s BNT162b2 vaccine obtained the emergency authorization from FDA, becoming the first mRNA drug approved for human body. A week later, the Moderna vaccine mRNA-1273 was also authorized for use in the United States. In the end, they were the first SARS-CoV-2 vaccines authorized in the United States, Britain, Canada and several other countries.
Pfizer and BioNTech jointly developed five mRNA candidate vaccines, which encode variants of spike protein antigen. Two main candidate drugs, BNT162b1 and BNT162b2, use ionized lipid ALC-0315 of Acuitas Therapeutics and nucleoside modified mRNA, in which all uridine is replaced by N1 methyl pseudouridine to enhance mRNA translation. BNT162b1 encodes the receptor binding domain of trimeric secretory spinous protein, while BNT162b2 encodes the full-length SARS-CoV-2 spinous protein, and two proline substitutions in S2 subunit lock the protein in the pre-fusion conformation.
In the first trial of the two vaccines, both of them can induce neutralizing antibodies with high titers, and produce strong CD4+ and CD8+ reactions, accompanied by mild to moderate adverse reactions. The two candidate vaccines were well tolerated and effective, but only BNT162b2 vaccine entered the phase II/III trial because of its mild systemic and local adverse reactions. In the third phase of the trial, BNT162B2 showed 95% overall prevention and 90 ~ 100% curative effect.
Moderna cooperated with the National Institutes of Health to develop mRNA-1273. The vaccine uses ionized lipid SM-102 to prepare LNP, which encapsulates the mRNA modified by N1 methyl pseudouridine. This sequence encodes SARS-CoV-2 spinous protein, with two proline substitutions, giving it a pre-fusion conformation.
In phase 1 clinical trials, mRNA-1273 was very effective and well tolerated. In the phase III trial involving 30,420 volunteers, the prevention rate of two 100μg vaccines was 94.1%, and local pain at the injection site was the most common side effect. After the second dose, half of the volunteers reported moderate to severe systemic side effects (
Such as fatigue, muscle pain, joint pain
), these side effects disappeared within 48 hours.
Although the vaccines produced by Pfizer and Moderna have been proved to have good efficacy and safety, their demand for cold chain storage has brought great difficulties to guarantee. MRNA-1273 can be stored at 4-8℃ for one month, while BNT162b2 needs to be stored at -60℃.
CVnCoV, the candidate vaccine of CureVac, can be stored stably for 3 months at 5℃. CVnCoV uses Acuitas Therapeutics (
It may be ALC-0315
) and unmodified mRNA encoding full-length spike protein with two proline substitutes. In the first phase of clinical trial, the neutralizing antibody produced by volunteers was similar to that of patients with CVID-19 in recovery period and was well tolerated. Unfortunately, however, in phase III clinical trials involving 40,000 people, CVnCoV only showed 47% efficacy. Mid-term analysis shows that the low curative effect of CVnCoV is attributed to the new SARS-CoV-2 mutation.
At present, CureVac is cooperating with GSK to develop the second generation candidate drug-C2CoV, which has been optimized to enhance its translation and immunogenicity compared with CVnCoV. CV2CoV uses 5’UTR from human hydroxysteroid 17-β- dehydrogenase 4 gene and 3’UTR from human proteasome 20S subunit β3 gene. In preclinical studies, the protein expression of CV2CoV was 1.8 times higher than that of CVnCoV in vitro, and high-titer cross-neutralizing antibodies against B.1.1.7, B.1.1.298 and B.1.351 variants were induced in rats.
Another heat-resistant candidate vaccine, ARCoV, was developed by PLA Academy of Military Sciences in cooperation with Walvax Biotechnology Company, and can be stable at 25℃ for one week. ARCoV encodes the receptor binding domain of spike protein. In preclinical studies, high SARS-CoV-2 specific IgG antibody and strong virus neutralization titer can be induced in cynomolgus monkeys. Although the reasons behind the thermal stability of CVnCoV and ARCoV are not clear, the secondary structure of mRNA, smaller mRNA size, GC content and lipid may be important factors.
Other mRNA candidate vaccines are also under development. LNP-nCoVsaRNA was jointly developed by Imperial College London in London and Acuitas Therapeutics, encoding the full-length spike protein. At present, the phase I clinical trial evaluation is being carried out using the dose escalation scheme of 0.1–1g (
ISRCTN17072692
), which uses the lowest RNA dose among all candidate mRNA vaccines.
Another self-amplified mRNA vaccine candidate ARCT-021 (
Also known as LUNAR-COV19
) by Arcturus company using its proprietary LUNAR lipid carrier and self-transcription and replication RNA (
STARR
) platform development. It encodes a full-length fusion pre-spike protein.
Influenza virus vaccine
About 290,000 to 650,000 people worldwide die from influenza virus every year. At present, the vaccine targets the viral hemagglutinin protein that promotes the entry of the virus. The traditional influenza vaccine is an inactivated influenza virus growing in eggs, which takes a long time to produce and is difficult to purify. In addition, viruses mutate in eggs for optimal growth, sometimes rendering them ineffective in humans.
Therefore, alternative antigen targets and production methods are really needed. Synthetic mRNAs transcribed in vitro can meet this demand and ensure the rapid production of vaccines when new influenza strains appear. For example, in 2013, based on LNP (
DLinDMA
) was successfully developed within 8 days after the outbreak of H7N9 in China, but unfortunately, clinical trials could not be conducted because there was no GMP facility for mRNA manufacturing at that time.
Some people are also committed to developing a universal influenza vaccine that does not need to be revised every year. This vaccine can produce immunity to several influenza virus strains and subtypes. The influenza mRNA vaccine, which was first displayed in 2012, induced homologous and heterologous immunity against H1N1 and H5N1 strains in mice by three intradermal injections.
It is worth noting that the conserved region of hemagglutinin, which is not easy to mutate, has recently become a new universal vaccine target. Another study used LNPs to deliver 50ng dose of mRNA, encoding three conserved influenza proteins: neuraminidase, nucleoprotein and matrix -2 ion channel protein, and hemagglutinin stem region. Incredibly, this tiny dose of mRNA produced a wide range of protective antibodies.
Zika virus vaccine
Zika virus infection was first discovered in 1947. Patients infected with Zika virus usually have no symptoms or mild symptoms such as fever, rash and muscle pain. However, Zika virus became a global health crisis during the American epidemic in 2015-2016, which caused severe fetal neural malformation and fetal death during pregnancy. Membrane and envelope protein (
prM-E
) is a common antigen selection for mRNA vaccine against Zika virus, because neutralizing antibody against prM-E can prevent virus fusion.
Moderna cooperated with Washington University School of Medicine to develop an improved prM-E mRNA, which contains the mutant fusion circular epitope in E protein. Two 10μg doses of mRNA can protect mice from Zika virus attack and reduce the production of dengue enhanced antibodies. These encouraging preclinical results promoted the phase I trial, and the interim results showed that the vaccine mRNA-1893 induced 94-100% seroconversion within 10 days, which was well tolerated.
In addition, another study used passive immunization method to deliver mRNA encoding ZIKV neutralizing antibody using squalene-based nanocarriers. This is an attractive method for immunocompromised patients whose immune system is damaged and unable to synthesize autoantibodies.
HIV vaccine
Globally, HIV currently affects 38 million people and is expected to affect as many as 42 million people by 2030. Although the research has been carried out for 30 years, no effective vaccine has been developed, mainly because of the significant antigenic diversity of HIV envelope proteins and the hidden "glycan barrier" of key envelope protein epitopes. Several preclinical studies have used a variety of carriers, including cationic nanoemulsion, DOTAP/DOPE liposome, Polymers and ionizable LNP, and they have seen some effects in different degrees. These studies show that in addition to effective vectors, new antigens are crucial for effectively targeting HIV.
Respiratory syncytial virus vaccine
Respiratory syncytial virus is the main cause of acute lower respiratory tract infection in the world. Every year, it is estimated that 60,000 children under the age of 5 die and more than 14,000 people over the age of 65 die.
At present, RSV candidate vaccines mainly target highly conserved F protein. Although some candidates failed to pass the clinical trial because of insufficient neutralizing antibody titer, the new discovery of F protein conformation shows that vaccination against pre-fusion conformation can produce excellent neutralizing antibody reaction. This discovery is expected to improve the future vaccine design.
Moderna is evaluating three single-dose candidate vaccines encoding pre-fusion F protein: mRNA-1172 and mRNA-1777 for adults, and mRNA-1345 for children. In the phase I clinical trial, mRNA-1777 induced a strong humoral response of RSV neutralizing antibody, and CD4+T cells reacted to RSV F protein without serious adverse events. The sequence of mRNA-1345 has been further designed and codon optimized to enhance the translation and immunogenicity relative to mRNA-1777. One month after inoculation, the titer of neutralizing antibody produced by mRNA-1345 was about eight times that of mRNA-1777. Finally, the goal of Moderna is to combine mRNA-1345 with pediatric human metapneumovirus/parainfluenza virus type 3 (
hMPV/PIV3
) Candidate vaccine mRNA-1653 was integrated, and children were vaccinated against three different pathogens with a single formula.
Ebola virus vaccine
Ebola virus (
EBOV
) was first identified as the pathogen that caused the Ebola outbreak in 1976. This viral hemorrhagic fever claimed more than 11,000 lives in the Ebola epidemic in West Africa in 2014-2016. In 2019, FDA approved a recombinant vesicular stomatitis virus (
VSV
) Ebola vaccine (
rVSV-EBOV
)。 Although the effectiveness of rVSV-EBOV in preventing the spread of Ebola is 97.5% compared with that without vaccination, clinical trials have noticed some safety problems (
Such as acute arthritis and rash.
)。
Anti-EBOV mRNA vaccines may be safer than this virus-based vaccine because they will not replicate in vivo. An mRNA vaccine encoding EBOV glycoprotein has been proved to be effective in mice. The vaccine can induce the strong expression of glycoprotein-specific IgG antibody, IFN-γ and IL-2 through CD8+ and CD4+T cells, which can protect animals from deadly virus.
Rabies virus vaccine
Rabies is a zoonotic disease, characterized by neurological symptoms, with a mortality rate of nearly 100%. Although vaccines have been approved, more than 50,000 people still die of rabies every year, which highlights the need for more effective and cheaper vaccines.
In order to meet this demand, CureVac used its RNActive platform to screen the unmodified mRNA vaccine CV7201 encoding rabies virus glycoprotein. In a preclinical study, CV7201 can induce high neutralizing antibody titers in mice and pigs, and induce antigen-specific CD4+ and CD8+T cell responses. However, in the phase I clinical trial, it was found that although the route of administration did not affect the immune response, only the intradermal syringe produced a short-term humoral immune response. This weak drug delivery effect and high incidence of adverse events indicate that the drug delivery platform needs to be further optimized.
Subsequently, CureVac used the proprietary LNP produced by Acuitas Therapeutics as the carrier of its new vaccine CV7202. In a preclinical study, CV7202 induced strong antibody titers and CD8+ and CD4+T cell responses. The results of phase I clinical trials show that two 1g doses can produce high titer neutralizing antibodies and strong adaptive immune response, which is well tolerated.
Malaria vaccine
Although the vast majority of mRNA vaccines under development are aimed at preventing virus infection, there are also efforts to prevent other infectious diseases. Malaria is caused by unicellular eukaryotic parasites, and its incidence and lethality rank first. Every year, malaria afflicts more than 200 million people around the world and kills more than 400,000 patients. Due to the lack of surface antigen and the complex life cycle of plasmodium, the production of antimalarial vaccine has been difficult. Fortunately, the study of human natural immune response to plasmodium infection has identified potential non-surface antigen targets.
For example, the cytokine macrophage migration inhibitory factor secreted by plasmodium (
PMIF
) has been proved to prevent T cells from producing long-term memory. According to this discovery, a vaccine was prepared from squalene-based cationic nanoemulsion loaded with self-amplified mRNA encoding PMIF. Two doses of 15μg can improve the development of helper T cells and induce anti-plasmodium IgG antibody and memory T cell response.
Another study on the mechanism of malaria infection found that Plasmodium falciparum is rich in glutamate protein (
PfGARP
) is a potential target of mRNA vaccine. A nucleoside modified mRNA vaccine encoding PfGARP antigen is being developed, which uses LNP proprietary to Acuitas Therapeutics. Preclinical studies show that the vaccine can reduce the reaction of animals infected with plasmodium.
Key problems of mRNA vaccine
At present, there are still many doubts about the safety of mRNA vaccine. In addition, the mRNA vaccine has been approved only in the prevention of SARS-CoV-2, and its efficacy in other aspects needs further study. Many problems need to be solved. Let’s discuss some key problems that mRNA vaccine may face in the future.
Antigen reaction duration
After vaccination, antigen is absorbed by antigen presenting cells and transported to lymph nodes, where B cells, antigen presenting cells and follicular helper T cells (
Tfh
) promote the formation of germinal center. In the germinal center, B cells then proliferate, differentiate and mutate their antibody genes to produce high affinity neutralizing antibodies against aggressive antigens. Germinal center reaction and Tfh cell induction are very important for lasting antibody response, which will protect patients for months or years.
In order to enhance the first step of this immune response process, some delivery systems target antigen-presenting cells and translate mRNA. Several promising strategies for actively targeting antigen presenting cells include binding monoclonal antibodies to LNP surface and modifying LNP surface with dendritic cell-specific ligands. Alternatively, regulating the physical properties of LNP, such as surface charge, has been used to improve the efficacy of cancer vaccines.
In addition, changing vaccine pharmacokinetics by prolonging the translation of antigen mRNA has become an exciting tool to enhance antibody response. Continuous availability of antigen during germinal center reaction has been proved to increase antibody production by about 10 times. A study in mice showed that compared with unmodified mRNA, nucleoside-modified mRNA had a longer circulating time and induced a stronger reaction between Tfh cells and B cells in germinal center.
In clinical trials, two doses of mRNA-1273 can also trigger a lasting antibody response within 6 months. Although the antibody titer decreased slightly during the study period, all age groups maintained high neutralization ability. These results are promising, however, the duration of antibody reaction is a complex phenomenon, and different antigens will be different, which requires longer data to fully understand.
Mutations against viruses
Mutations in viral genomes are common in the process of replication. Although most mutations have little or no effect on the function of the virus, some mutations can enhance immune evasion and hinder the development of vaccines. For example, for more than 30 years, the rapid mutation of HIV has hindered the development of effective vaccines, while the mutation of influenza virus needs to modify the vaccine formula every year to target the dominant strains.
The emerging SARS-CoV-2 mutation has also attracted attention to the effectiveness of cross-mutation of mRNA vaccine. Variants B.1.351 and P.1 are located at position 484 of spinous protein receptor binding domain (
E484K
) glutamic acid exists (
E
) to lysine (
K
) mutation, which promotes immune escape. Fortunately, FDA-approved mRNA vaccines BNT162b2 and mRNA-1273 produced cross-neutralizing antibodies against B.1.351 and P.1 and other variants, which indicated that they could provide protection against them. However, compared with the original virus, the cross neutralization effect has been significantly reduced. In addition, in the IIb/III trial of CureVac’s candidate CVnCoV, 57% of the 124 COVID-19 cases sequenced were mutants, including B.1.351 and P.1 variants.
If these mutant strains gradually become major variants over time, variant-specific mRNA enhancers may be needed. At present, Moderna is evaluating the original mRNA-1273 vaccine and the latest version as the third booster: mRNA-1273.351, which encodes spinous protein from variant B.1.351, and mRNA-1273.211, a 1:1 mixed vaccine of mRNA-1273 and mRNA-1273.351.
In the long run, it will be more beneficial to provide a pan-coronavirus vaccine to protect SARS-CoV-2 and future coronavirus outbreaks. Like HIV and influenza, new structural insights are expected to promote the discovery of conserved sites of coronavirus and accelerate antigen discovery and vaccine design.
security
Generally speaking, mRNA vaccine has good safety, and only mild or moderate adverse events occurred in clinical trials. However, there are also individual events that require further optimization of mRNA antigens and vehicle components. For example, CureVac’s protamine-based rabies candidate drug CV7201 caused serious adverse events in 78% of the participants, prompting CureVac to adopt LNPs as the first choice for its subsequent rabies candidate drug CV7202.
Like most drugs, the adverse reactions of mRNA vaccine often increase with the increase of dose. For example, in the first phase test of CV7202, 5μg dose has unacceptable toxicity, while 1μg is the highest dose with good tolerance. In addition, in the first phase trial of Moderna H10N8 influenza vaccine, serious adverse events appeared in patients with a dose of 400μ g, so the trial continued with a dose of 100μg g..
When using the COVID-19 vaccines of Pfizer-BioNTech and Moderna, allergic reactions were observed in about 4.7 parts per million and 2.5 parts per million, respectively, which was about 2-4 times that of the traditional vaccination. One view is that allergic reactions are attributed to pre-existing antibodies against PEGylated lipids in LNP. These antibodies are considered to be effective against many consumer products (
Such as toothpaste, shampoo and laxatives.
) has a reaction with PEG. It is reported that 40% people have anti-PEG antibodies, which may increase the risk of allergic reactions in some individuals and hinder the effectiveness of vaccines. At present, CDC recommends that individuals who have a history of allergy to any component of Pfizer-BioNTech or Moderna vaccine should not use mRNA vaccine. Obviously, we need to better understand how the mRNA vaccine formula causes allergic reactions, so that we can redesign the formula to improve safety.
Vaccination of specific population
Most vaccines, whether traditional vaccines or mRNA vaccines, are developed for children or healthy adults. However, due to different immune systems, some people may benefit from alternative vaccination strategies or have different responses to vaccination.
Maternal/neonatal vaccination
The dynamic characteristics of the immune system during pregnancy increase a person’s susceptibility to infectious diseases, and infection will have a disastrous impact on maternal health and fetal development.
In order to meet these challenges, maternal vaccination has become a tool to improve maternal health and reduce neonatal morbidity. Maternal IgG antibody can easily cross the placenta and enter the fetal circulation by binding to the neonatal Fc receptor, thus protecting the fetus from pathogens. In several studies, maternal inoculation with mRNA-loaded LNPs can prevent the spread of fetal Zika virus in pregnant mice and protect newborn mice from herpes virus and streptococcus infection.
Although vertically transferred maternal antibodies can prevent neonatal infection, they will also hinder the effect of vaccination for infants in later life, and the mechanism is still unclear. Prolonging the availability of antigen may promote a stronger germinal center response, thus producing a strong infant immune response in the presence of maternal antibodies.
The anti-SARS-CoV-2 mRNA vaccine has also been proved to be immunogenic to pregnant and lactating people, and neutralizing antibodies have been detected in cord blood and human milk. Preliminary data show that mRNA-1273 and BNT162b2 cause similar adverse events in pregnant and non-pregnant people, and the vaccine will not increase the incidence of neonatal death or congenital abnormalities. However, further longitudinal studies are needed to evaluate the impact of mRNA vaccine on maternal and neonatal health.
the aged
This group is in urgent need of effective vaccines, because many infectious diseases affect the elderly. For example, 70 to 90% of influenza-related mortality occurs in patients over 65 years old, while the mortality rate of COVID-19 is 62 times that of young patients over 65 years old.
It is more difficult for the elderly to be vaccinated, because aging has an adverse effect on both innate and adaptive responses of the immune system. The decrease of Toll-like receptor expression will prevent monocytes and macrophages from secreting cytokines and chemokines, and limit the crosstalk with adaptive immune system. The adaptive immune response during infection is usually insufficient due to impaired cytokine signals and physiological and cellular changes. These changes include thymus degeneration, the decrease of naive B cells and T cells, the decrease of T cell receptor diversity, the higher susceptibility to T cell apoptosis, and the decrease of the expression of key receptors such as CD28 on cytotoxic CD8+T cells.
Fortunately, more and more evidence shows that mRNA vaccine may have strong efficacy in all age groups. For example, in the phase III trial, the efficacy of BNT162b2, a candidate vaccine of Pfizer-BioNTech, exceeded 93% in all treatment groups. The candidate vaccine of Moderna, mRNA-1273, is also very effective, showing 86.4% effectiveness in volunteers over 65 years old, compared with 95.6% in volunteers aged 18-65 years old.
The design of delivery tools is very important to improve the efficacy of vaccines for the elderly. MRNA vector can be used as an inflammatory adjuvant to amplify the vaccine response by enhancing the recruitment of antigen-presenting cells to the injection site. In a preclinical study, CureVac’s RNAVAC activated TLR7 and produced a lasting immune response against deadly influenza in mice. Novartis emulsion MF59 has been used as mRNA delivery carrier and adjuvant. MF59 enhances the immunogenicity of influenza vaccine and has been approved for the elderly.
Acquisition of vaccine
Obtaining vaccines is the biggest challenge to achieve widespread prevention of infectious diseases, especially in low-income countries. The cold storage requirements of the approved SARS-CoV-2 mRNA vaccine further limit the acquisition of the vaccine. Portable and reusable Arktek freezer can realize the rapid deployment of millions of doses of vaccine during an epidemic.
However, the COVID-19 virus needs to vaccinate billions of people, which requires a heat-resistant vaccine. At present, there are two candidate vaccines of SARS-CoV-2 with heat tolerance at room temperature. If these candidate vaccines can show good results in clinical trials, they may simplify the global acquisition of mRNA vaccines in the near future.
Acceptance of vaccine
Vaccines are only effective after vaccination, and there are abundant data supporting the safety and effectiveness of vaccines. Vaccines have eradicated several infectious diseases in some parts of the world and saved countless lives. However, due to misinformation and anti-vaccine campaigns, public distrust has intensified, threatening the maintenance of group immunity and putting our most vulnerable people at risk.
The decline in vaccination coverage may lead to the re-emergence of life-threatening diseases. For example, measles eradicated from the United States in 2000 infected more than 1,200 people in 2019 because of poor vaccine compliance in many communities. For COVID-19, in the United States, the current acceptance rate of 56-75% may not be enough to reach at least 80-90% coverage, and this threshold is considered to be necessary for SARS-CoV-2 population immunization.
Although most of the burden of improving vaccine coverage falls on the government and public health officials, the scientific community can also help by improving the effectiveness and safety of mRNA vaccines. Improving the curative effect will reduce the acceptance of group immunization, and improving safety will prevent the media from reporting adverse events, thus reducing the fear of vaccination.
summarize
In the past decades, the progress of mRNA design and nucleic acid delivery technology, coupled with the discovery of new antigen targets, has made mRNA vaccine an extraordinary tool to fight emerging epidemics and existing infectious diseases. Two mRNA vaccines against SARS-CoV-2 were developed at revolutionary speed and provided excellent protection rate, which is expected to end the COVID-19 pandemic.
In addition, these vaccines promote LNP and RNA therapy from niche market products to preventive treatment successfully implemented in a large number of people. As a result, a large number of safety and effectiveness data, as well as successful regulatory approval. We can be optimistic that mRNA therapy will probably change the vaccination methods, cancer immunotherapy and protein replacement therapy in modern medicine.
References:
1. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat RevDrug Discov. 2021 Aug 25 : 1–22.
2. Recent advances in mRNA vaccine technology. Curr Opin Immunol. 2020 Aug; 65:14-20.

Spring Festival travel rush train tickets will be on sale tomorrow: it is estimated that 280 million passengers will be sent, and the ticketing time will be extended.

  On January 2, The Paper reporter learned from China National Railway Group Co., Ltd. (hereinafter referred to as "China State Railway Group Co.,Ltd.") that in 2022, the railway Spring Festival travel rush will start on January 17 and end on February 25, with a total of 40 days, and the national railway is expected to send 280 million passengers, with a year-on-year increase of 28.5%. According to the arrangement that the train tickets will be sold 15 days in advance, on January 3, 2022, the railway department will start to sell the 2022 Spring Festival travel rush train tickets.

  According to the person in charge of the Ministry of Transport of China State Railway Group Co.,Ltd., in 2022, the railway Spring Festival travel rush will face multiple challenges, such as accurate epidemic prevention and control, Beijing Winter Olympics transportation guarantee, etc. The situation is complex and changeable, and the transportation service organization is more difficult. The railway department will conscientiously implement the work arrangements of the CPC Central Committee and the State Council during the New Year’s Day and Spring Festival, adhere to the people-centered development idea, make overall plans for development and safety, make overall plans for epidemic prevention and control and Spring Festival travel rush organization, and make overall plans for transportation security in Spring Festival travel rush and Winter Olympics, earnestly do a good job in Spring Festival travel rush, constantly improve the sense of security, acquisition and happiness of the vast number of passengers, provide high-quality transportation service guarantee for the Winter Olympics, and strive to achieve the goal of "Safe Spring Festival travel rush, orderly Spring Festival travel rush, warm Spring Festival travel rush, and better passenger experience".

  First, adhere to the arrangement of needs, emergency preparedness, accurate matching, ladder delivery, and accurately arrange passenger transportation capacity. Make full use of the transportation advantages of the developed and perfect railway network and modern high-speed rail network, especially the newly added lines and EMU resources in the first year of the "14th Five-Year Plan", and specially draw the train operation map of Spring Festival travel rush. The passenger capacity can meet the transportation demand under strict epidemic prevention and control. Before Spring Festival travel rush, new lines such as China-Laos Railway, Ganshen, Anjiu, Zhangjihuai, Mujia, Hangtai and Rilan high-speed railway were opened for operation, which further enhanced the transportation capacity of Yunnan, Jiangxi, Anhui, Hunan, Heilongjiang, Zhejiang and Shandong. The south section of the Beijing-Hong Kong high-speed railway from Nanchang to Shenzhen runs through the whole line, which greatly shortens the time and space distance between the central and eastern cities such as Nanchang, Hefei, Nanjing and Shanghai and the Guangzhou-Shenzhen area, and will effectively facilitate the people along the line to travel in Spring Festival travel rush. The railway department will accurately analyze the passenger demand according to the changes in the epidemic prevention and control situation, the pre-sale of tickets and the data of alternate ticket purchase, determine the timing of train launch and passenger start-up, and put the capacity in steps. At the same time, maintain the necessary scale of ordinary speed trains, make overall plans for trains in the direction where passenger flow is not concentrated, and insist on running public welfare slow trains to ensure the basic travel of passengers.

  The second is to adapt to the rules of passenger travel under the conditions of epidemic prevention and control, and improve the service measures of ticket sales and return and change. Coordinate the precise requirements of epidemic prevention and control and the convenient travel needs of passengers, and continuously improve service measures to facilitate passengers to purchase tickets and return and change their visas. Extend the ticketing service time of 12306 website (including mobile phone client) from 5:00 to 23:30 every day to 5:00 to 1:00 the next morning (except every Tuesday); Provide 24-hour Internet refund service, the deadline for refund is extended from 25 minutes before the bus stop starts to before the bus stop starts, and 12306 client login-free refund channel is added; Add online processing channels to the business of changing the ticket after driving, which can only be handled at the ticket issuing station, and add the function of changing the electronic ticket at the self-service ticketing terminal; Adjust the latest deadline for standby ticket purchase from 6 hours before driving to 2 hours; Provide passengers with temporary electronic identification.

  Third, take the initiative to meet the demand and do a good job in ensuring the transportation service of the Winter Olympics with high quality. The Beijing-Zhangjia High-speed Railway has arranged 40 pairs of winter Olympic trains and special trains for the opening and closing ceremonies. Research and develop the online 12306 English website, English client and English self-service ticket vending machine, support foreign credit cards such as VISA and JCB to purchase tickets, and add the ticketing service function in the Winter Olympics area to strengthen ticketing and service guarantee for the Winter Olympics.

  Fourth, scientifically and accurately implement epidemic prevention and control measures, and resolutely prevent the epidemic from spreading through railway Spring Festival travel rush. In accordance with the joint prevention and control mechanism in the State Council and the policy requirements of precise prevention and control in various places, the epidemic prevention and control measures in the whole process of passenger travel are strictly implemented. In the ticketing process, strictly control the passenger load rate of trains and implement decentralized ticketing in qualified trains; In the ride, guide passengers to wait at the station in an orderly manner, do a good job of temperature measurement and code inspection in strict accordance with the requirements of the local government, and prevent passengers who do not meet the ride requirements from entering the station; In the train operation, strengthen the broadcasting and publicity of station cars, reserve isolated seats according to regulations, and do a good job of disposal in a scientific and orderly manner once passengers involved in the epidemic are found. Strictly implement the overall plan for epidemic prevention and control of Beijing Winter Olympics and Winter Paralympics, and implement closed-loop and non-closed-loop management for 55 days from January 21 to March 16 for the four winter Olympics service stations of Beijing-Zhangjia high-speed railway Qinghe, Yanqing, Prince City and Chongli, so that closed-loop personnel and ordinary passengers do not intersect; For special carriages and special trains for transportation services in the Winter Olympics, we will strictly do a good job in ventilation and disinfection, and earnestly do a good job in prevention and control of transportation support in the Winter Olympics.

  The fifth is to coordinate the supply of freight capacity and ensure the transportation of key materials for the national economy and people’s livelihood, such as coal. During Spring Festival travel rush, we will continue to strengthen the transportation of key materials related to the national economy and people’s livelihood, such as coal for power generation and heating, northeast grain, spring ploughing fertilizer and holiday materials, so as to ensure the warm winter of the people and the smooth operation of the national economy. Increase the supply of goods, loading and unloading power and machinery organization during the Spring Festival holiday, improve the working efficiency, and ensure that the national railways load more than 170,000 vehicles per day, and ensure that the 363 direct power supply plants in China can store coal for more than 15 days.

  The person in charge said that the railway department will timely allocate capacity according to the epidemic prevention and control requirements and passenger flow changes, dynamically adjust train operation, continuously improve service measures, and strive to enhance the travel experience of the majority of passengers. Passengers are requested to pay close attention to the information published on the "Railway 12306" website and "China Railway" WeChat WeChat official account in time and make reasonable arrangements for their trips.