Gao Fu, Eric Rubin, Fu Yangxin, Chen Xiaowei, Li Bin, etc.: Develop a new generation of high-efficiency Covid-19 vaccines and drugs to end the new crown epidemic

On April 14, 2022, the 14th NEJM Editor-in-Chief Forum "Latest Advances in Covid-19 Vaccines and Drugs" webinar organized by "NEJM Frontiers in Medicine" invited Chinese and foreign experts in the fields of immunization, virus and public health to discuss related academic hotspots
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These experts include: Professor Eric Rubin, Editor-in-Chief of the New England Journal of Medicine (NEJM), Professor Xiao Ruiping, Associate Editor of NEJM and Executive Editor of NEJM Frontiers in Medicine, Professor Gao Fu of the Chinese Center for Disease Control and Prevention, Institute of Microbiology, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine Prof.
Li Bin, Shanghai Institute of Immunology, Prof.
Benjamin Cowling, School of Public Health, University of Hong Kong, Prof.
Fu Yangxin, School of Medicine, Tsinghua University, Associate Prof.
Chen Xiaowei, School of Future Technology, Peking University, Prof.
George Siber, Johns Hopkins University School of Medicine, Chief of CanSinoBio Professor Zhu Tao, scientific officer,
etc.

In his speech, Professor Xiao Ruiping pointed out through a series of charts that the recent rapid increase in domestic Covid-19 cases and asymptomatic infections poses huge challenges to epidemic prevention.
Chinese scientists are working hard to develop various vaccines and drugs, including mRNA vaccines, which will be extremely important.
Great help to control the Covid-19 epidemic
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Dr.
Zhao Jianfei, deputy editor of "NEJM Medical Frontiers", said that the theme of this conference is to face the future, explore science, and end the epidemic as soon as possible
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In his speech, Eric Rubin praised the scientific research work of Chinese scientists and clinicians in the early days of the Covid-19 epidemic
.

He believes that the current epidemic has brought a huge impact on China.
We look forward to new tools and means to fight the epidemic, and hope that this seminar will bring new ideas
.

This academic seminar is divided into two parts: expert lectures and round table discussions
.

The expert lecture on vaccine and drug research progress was first reported by Academician Gao Fu on "The Design and Efficacy of the Covid-19 Protein Subunit Vaccine ZF2001"
.

Gao Fu first reviewed the coronavirus-related epidemics, and then introduced seven routes for the development of coronavirus vaccines, focusing on the protein subunit RBD dimer in coronaviruses, and the Covid-19 vaccine ZF2001 developed based on this
.

Animal experiments confirmed that ZF2001 vaccine can prevent infection caused by coronavirus and can reduce the degree of lung damage after virus infection
.

Clinical trials have confirmed that ZF2001 can effectively prevent symptomatic, severe Covid-19 and death with high safety
.

The vaccine is effective against delta, alpha, kappa and other variants
.

In response to the breakthrough infection of omicron variant strains, Academician Gao Fu pointed out that the interval between vaccination of the third dose of booster vaccine should be extended, and different types of vaccines should be administered, such as the first two doses of virus inactivated vaccine, and the third dose of ZF2001 protein subunit.
Vaccines are better for prevention
.

Prof.
Benjamin Cowling reported the preventive effect of BNT162b2 vaccine and Kexing inactivated vaccine against omicron mutants in the fifth wave of the epidemic in Hong Kong
.

Similar to the situation in mainland China, the vaccination rate of the elderly population in Hong Kong is generally low
.

Among those who received two doses of the vaccine, the BNT162b2 vaccine had a certain preventive effect on mild to moderate Covid-19, while the inactivated vaccine was basically ineffective
.

After the third dose of the vaccine, the preventive efficacy of the BNT162b2 vaccine reached 71.
5%, and the inactivated vaccine increased to 42.
3%
.

In terms of preventing critical illness, the efficacy of two doses of BNT162b2 vaccine and inactivated vaccine was similar in young people, but in people over 80 years old, the efficacy of inactivated vaccine dropped to 60.
2%, while the protective efficacy of BNT162b2 vaccine still reached 84.
5%
.

When three doses of the vaccine were given, the protective efficacy of the two vaccines was similar
.

When it comes to preventing death, even a single dose of the vaccine provides some degree of protection
.

A third dose of the vaccine provided high protective efficacy regardless of age
.

Prof.
Fu Yangxin reported the design and efficacy of a new generation of Covid-19 protein fusion vaccine V-01
.

V-01 fuses INF-α, Pan, RBD and Fc to construct a vaccine, which can induce high levels of neutralizing antibodies at very low dose levels, and can be administered in a single dose without the need for special adjuvants
.

Animal experiments have shown that V-01 can induce a strong immune response and can protect experimental animals from new coronavirus infection
.

Moreover, the vaccine has the potential to be used for nasal mucosal immunization, thereby changing the immunoprophylaxis strategy
.

Phase 1 clinical trials confirmed that two doses of V-01 induced high levels of neutralizing antibodies
.

In addition, for those vaccinated with two doses of inactivated vaccine, booster vaccination with V-01 can effectively prevent the symptoms caused by the omicron variant
.

The title of Professor Chen Xiaowei's report is "Host-Targeted Novel Drugs Inhibit Coronavirus"
.

In the report, Professor Chen Xiaowei pointed out that the replication of coronaviruses in the human body depends on the double-layer lipid membrane structure.
The transmembrane flippase encoded by TMEM41B is likely to be the most important host factor for virus infection.
Without TMEM41B, the virus cannot infect the human body
.

Although TMEM41B cannot be a therapeutic target, its related pathways may become a therapeutic target
.

Through a series of drug screenings, Chen Xiaowei's laboratory found that the drug propranolol for the treatment of arrhythmia can inhibit the upstream enzyme of TMEM41B, thereby playing a role
.

Animal experiments have confirmed that propranolol can destroy the organelles on which virus replication depends, block virus replication, and reverse the pathophysiological outcome of coronavirus infection
.

In addition, low-dose propranolol in combination with antiviral drugs is effective against viruses and reduces viral load
.

Exploring future research directions In the roundtable discussion session, the host of the meeting, Professor Li Bin, first invited the participating experts to discuss the role of mucosal immunity in the prevention of infection by the new crown vaccine
.

Professor George Siber first pointed out that the existing vaccines are more effective in preventing severe disease, but it is difficult to prevent asymptomatic infections
.

Only by developing a vaccine that can prevent asymptomatic infection and block the spread of the virus will it be possible to control the epidemic
.

In this regard, vaccines that induce mucosal immunity have the potential to play a role
.

Professor Zhu Tao mentioned that CanSino has developed a viral vector-based nasal mucosa vaccine and has completed preliminary clinical trials
.

The results show that this type of vaccine can induce better humoral and cellular immune responses, and the induced neutralizing antibodies against delta and omicron are 16-20 times higher than those in the control group, and the level of IgA in saliva is also higher
.

Eric Rubin mentioned that a study published by NEJM last year found that after vaccinating people who recovered from coronavirus infection, the neutralizing antibodies produced by them can effectively fight against a variety of coronaviruses (see "Zhang Wenhong, Ying Tianlei Comments | SARS survivors" for details Vaccination against the new crown virus produces broad-spectrum neutralizing antibodies against a variety of coronaviruses”)
.

Fu Yangxin pointed out that the combination of delta and beta mutants to develop a bivalent vaccine will likely become the broadest SARS-CoV-2 vaccine, because these two mutants cover 80% to 90% of the antigenic epitopes, He speculates that this type of bivalent vaccine can also protect against some potential new variants in the future
.

Chen Xiaowei pointed out that the effective management of long-term infection of the new coronavirus is extremely important
.

Fu Yangxin believes that long-term infections of the new coronavirus are mostly immunocompromised patients, such as tumor patients, who may carry the new coronavirus in their bodies for a long time
.

For these patients, vaccination may not be effective, and even repeated booster vaccines cannot induce an immune response
.

In addition, some patients still have persistent virus infection despite receiving booster immunizations, and virus recombination may occur in these patients, accelerating the emergence of virus mutant strains
.

He believes that therapeutic drugs are extremely important for this group of patients
.

Eric Rubin pointed out that long-term infection of the new coronavirus often has persistent symptoms, and there is currently no clear definition, but the evidence of active viral replication in these patients is very limited
.

If a therapeutic drug were to be developed, it would most likely be a host-targeted drug rather than an antiviral drug
.

Antiviral drugs can only play a role in the early stage of infection.
After a week of infection, neither monoclonal antibodies nor small molecule drugs are effective
.

We use antiviral drugs in a very narrow time window, and may also need to develop therapeutic strategies along the lines of how to modulate host responses
.

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