Vaccine
magazine, recently mentioned the two most worrying questions about the development of COVID-19 vaccines: whether vaccines can enable vaccinators to produce enough and lasting antibodies, and how to avoid the enhancement effects of the disease caused by vaccines. His concerns are partly based on animal experimental data obtained from the development of SARS vaccine, and in addition, they are the tragic memories left by the RSV (respiratory syncytial virus) vaccine, a nemesis in the vaccine industry.
This article will mainly review the research and development process of the RSV vaccine in the past 60 years. COVID-19 and RSV are both single-stranded RNA viruses, and the consequences of both infection are viral pneumonia. The development of RSV vaccine may bring us some inspiration. After this article, "R&DK" will continue to write an article to introduce the global development of
COVID-19 vaccine , as well as the key issue related to the success or failure of COVID-19 vaccine clinical research endpoint selection, which is closely related to the success or failure of R&D, in order to present readers with a relatively complete COVID-19 vaccine development status.
Tragedy quietly came
RSV was discovered in 1957, and the vaccine development was launched shortly thereafter. The world's first product to enter clinical research is Pfizer's RSV formalin inactivated vaccine . At that time, the conventional means of vaccine preparation were deactivated or inactivated. Vaccines such as measles and polio were successfully developed in the same era, so the clinical research of RSV inactivated vaccine has not received special attention.
However, this time it was bad luck. This vaccine not only does not protect the vaccinated person, but instead has disease enhancement effect (ERD, disease enhancement, that is, vaccination will cause the vaccinated people to be more sensitive to the next infection or infection of other viruses) . Several studies conducted before and after observed that the subjects had a worsening of reinfection with RSV. In one study, 16 of the 20 infants in the trial group had severe symptoms and needed hospitalization, with an hospitalization rate of up to 80%. Two of them died at 14 and 16 months of infants, while only 1 in the 21 subjects in the control group were hospitalized. In this regard, FDA urgently stopped clinical research of all RSV vaccines and required that all RSV vaccines in the future need to provide evidence to prove that they will not have similar consequences before conducting clinical research.
This stop lasted for nearly 50 years. It was not until recently that partly understood that the possible reason for the enhanced disease is that the vaccine activates TH2-CD4+T cells, which leads to the occurrence of related cytokines mediated pneumonia, and this phenomenon is particularly prone to occur in infants and young children. At the same time, the researchers further found that the inactivated vaccine cannot induce the production of sufficient neutralizing antibodies to protect the vaccinator. All of these doomed that the RSV inactivated vaccine in the 1960s could only end in failure.
strikes one after another
The above ERD mechanism and the advancement of vaccine preparation technology have rekindled the enthusiasm of all sectors for the research and development of RSV vaccines in the new century, and even this product track has become a bit crowded now. Multinational pharmaceutical giants such as GSK and Jansen, as well as biotechnology companies such as Novavax and MedImmune, have joined the R&D cohort, and domestic companies Aidivixin Bio, South China vaccines, etc. have also launched similar projects.
rich new vaccine preparation methods, such as subunit vaccine, virus vector vaccine, nucleic acid vaccine and different types of adjuvants, have been introduced into the development of RSV vaccines, and some research institutions have also transformed the antigen that induces the body to produce immunity. At the same time, R&D personnel gradually summarized several important immune evaluation indicators for RSV vaccine screening, including being able to produce enough neutralizing antibodies, effectively activate CD8+T cells, and not activate TH2-CD4+T cells. Therefore, RSV subunit vaccine and viral vector vaccine are highly expected. Due to the relatively mature technology of the
subunit vaccine, clinical research on related products was the first to be launched. The F glycoprotein on the surface of the virus has a specific antigenic determinant and has been used as an important target for vaccine research and development. This protein has two structural phases, the pre-F structural phase before fusion with the host cell and the post-F structural phase after fusion. The pre-F is very unstable, and the problem of research and development also arises.Although there have been no serious adverse reactions in clinical research on subunit vaccines so far, bad news has been heard from early development of products in terms of protective power.
Novavax is the pioneer of the new round of RSV vaccine development. The antigens it has developed for the RSV F protein recombinant nanoparticle vaccine (ResVax) are relatively stable post-F. According to the data found on Clinicaltrials.gov, Novavax has launched 11 clinical studies since 2010. The subjects include the elderly, pregnant women, young women and children aged 2 to 6 years old.
The vaccine was a great success in the Phase II study involving 1,600 elderly people, and the market value of Novavax was once praised by enthusiastic investors to US$2.2 billion. However, this success did not extend to the end of Phase III. In September 2016, the company announced that the Phase III clinical trial of 11,856 elderly people aged 60 and above failed, and the results did not reach the primary and secondary clinical endpoint. At that time, some media reported that it was the biggest tragic clinical research event in 2016. The company's market value immediately shrank by 80% and was only US$300 million, causing some layoffs.
At the same time, Novavax still hopes that the study of protecting infants and young children through vaccination in late pregnancy has not achieved positive results. Because the protein recombinant nanoparticle vaccine still has the risk of ERD similar to inactivated vaccines, Novavax adopts a curved national saving strategy for infant vaccination, allowing mothers to produce antibodies and pass them to the fetus through the placenta. On February 28, 2019, Novavax announced that the vaccine's study in pregnant women had not reached its primary endpoint, with a total of 4,600 pregnant women participating in the four-year study, but the results were still not fulfilled.
In addition, MedImmune's MEDI-7510 also chose post-F as the vaccine antigen. The difference is that it added glucopyranose lipid A to the vaccine as an adjuvant, and the research on this product was also terminated in November 2016. A black cloud of vaccine development for post-F protein conformation is shrouded in.
, and the same type of vaccine developed based on pre-F is also bleak. GSK3003891A, a subsidiary of GSK, chose pre-F as the antigen, but due to the unstable structural structure of pre-F, the phase II study was terminated shortly after the completion of the Phase I clinical study and obtained preliminary results.
dawn first appeared
However, this recent series of failures has not stopped the pace of research and development. In order to solve the problem of Pre-F structural instability, Barney Graham et al. modified the protein structure, retaining the neutralization sensitivity epitope of the pre-F conformation of the F protein while increasing stability, and developed the RSV F DS-Cav1 (VRC317) vaccine.
August 2019 University of Texas announced that in a Phase I clinical study involving 40 subjects, interim analysis showed early hope that neutralizing antibodies produced by the VRC317 vaccine can last for several months. An article published in the 2019 Science magazine also showed that the increase in RSV neutralizing antibodies caused by VRC317 exceeded 10 times that of natural infection. It is predicted that the final results of this Phase I study will be announced in 2020.
In addition, the new generation of vaccine development technology - viral vector vaccine, is believed to be possible to crack the black hole of infant RSV vaccine development. Existing studies suggest that viral vector vaccines are less likely to produce ERD, and in terms of their mechanism, this type of vaccine can activate cellular and humoral immunity at the same time, both of which are favorable factors for the development of RSV vaccines suitable for infants and young children. Moreover, viral vectors can carry multiple antigen-expressing genes that trigger immune responses at the same time, not only limited to F proteins, but also enhance immune effects.
GSK has reshaped its RSV vaccine product line and shifted its focus to the development of chimpanzee adenovirus vector vaccine ChAd155-RSV (GSK3389245A). The vaccine has completed phase I safety research on adults, and the exploration of safety and effectiveness of infants and young children under 1 year old will begin at the end of 2019.
Another human adenovirus vector vaccine developed by Janssen is also being conducted in clinical trials in the elderly and infants. In view of the positive results achieved by the vaccine in the Phase II study of the Elderly, on September 3, 2019, the FDA awarded its Advanced Vaccine Breakthrough Drug Qualification (BTD) certification for the prevention of RSV-mediated lower respiratory tract disease in the elderly population aged 60 and above.
At this point, the dawn of RSV vaccine development has begun to emerge, but it is still hard to say that the future is smooth.In December 2019, the FDA approved the launch of the Ebola vaccine of the world's first viral vector vaccine, Merck's Ebola vaccine. It took 6 years since Merck obtained the vaccine research and development authorization in 2014, and more than 10 years have passed. From this, it is optimistic that the RSV vaccine under development will probably take several years to go on the market.
postscript
RSV vaccine has made full attempts to various vaccine technologies in the past 60 years of research and development, and has made a lot of research on the immune response produced by vaccines in the human body. Although there are still many mysteries to be solved, the lessons and experiences it has left behind still have a certain reference effect on the development of new coronavirus vaccines today, suggesting the challenges that may be encountered in the vaccine development process and which methods will help resolve the crisis.
Currently, global COVID-19 vaccine development is rapidly starting. Domestic companies CanSino, Smith Microbiology, and AiBobiology have all products entering the preclinical research stage. Foreign companies such as Moderna and GSK are also actively participating. The research and development directions of vaccines include inactivated vaccines, subunit vaccines, viral vector vaccines and nucleic acid vaccines.
and can the new crown vaccines of various preparation methods produce enough neutralizing antibodies, what is the protective power of the vaccine, and whether different vaccines should be designed for different groups of people, especially infants and young children? How to choose the target of a vaccine? The epidemic may disappear shortly after the outbreak. How should the clinical end point of the study be set? These were once mud pits that were developed by RSV vaccines. Now we still know very little about the new coronavirus, and we can only cross the river carefully with every step.
Both at home and abroad are eager for the emergence of vaccines, but science and ethics are also topics that cannot be avoided in the process of vaccine development, and some time is needed for research and development. The premature death of two babies 60 years ago should not be easily forgotten.
In the next article, we will try to summarize the domestic and international progress of the development of the new coronavirus vaccine.
Total 98877th issue
7http://www.thpcl.com thpcl.com thpcl.com thpcl.com station thpcl.com scan browsing view refresh more thpcl.com
