Written by | Yebin Zhou (Ph.D., University of Alabama at Birmingham)
On January 26, 2023, the U.S. Food and Drug Administration (FDA) convened a meeting of the Advisory Committee on Vaccines and Biologics. At the meeting, outside independent scientists convened by the FDA voted in favor of phasing out monovalent vaccines based on the original virus strain and completely switching to bivalent vaccines containing Omicron antigens. In addition, the meeting also discussed the future process of updating the new crown vaccine and the development direction of future vaccines. So why did the U.S. government change vaccines, and what information did this meeting reveal about the future development of new crown vaccines?
01 "Phasing out" the original vaccine: solving the problem at hand
In the fall of 2022, the new crown mRNA vaccine was updated for the first time, and the bivalent vaccine was launched as a new booster. This bivalent vaccine consists of half of the dose of the original strain of the vaccine and the other half of the updated vaccine containing the Omicron spike protein sequence. There are two versions of the specific Omicron sequence, with only BA.4/5-based bivalent vaccines used in the United States and BA.1-based bivalent vaccines available in other parts of the world.
It is worth noting that the bivalent vaccine is only used for booster shots after its introduction, and an unvaccinated person still needs to use the original vaccine for primary immunization. At that time, why not just completely replace the original vaccine with a bivalent vaccine? There are multiple considerations here.
First of all, in terms of primary immunization, the original vaccine is supported by a large number of efficacy and safety data, while the main data relied on when the bivalent vaccine was launched came from the BA.1 version of the booster shot test in humans and the BA.4/5 version of the booster shot test in animal models. To be directly promoted to primary immunization, the data are not perfect.
Second, in the booster clinical trial at that time, the BA.1 version of the bivalent vaccine induced Omicron neutralizing antibody titer (against the BA.1 substrain) was only about 1.75 times that of the original vaccine [1]. The limited degree of improvement means that the bivalent vaccine is not a "earth-shaking" improvement, which makes it unnecessary to rush to completely replace the original vaccine with the bivalent vaccine.
Third, some animal experiments have shown that the monovalent Omicron vaccine is not much better than the original vaccine in terms of immune response and attack protection against the Omicron virus strain (the experiment is vaccinated and then infected with the virus to test the protective effect) [2], which also makes regulators and the medical community more cautious about the comprehensive switch to bivalent vaccines.
Based on these data at that time, the WHO, FDA, etc. all chose to use Omicron bivalent vaccine as a booster shot without changing the composition of the primary immunization vaccine, which is a more prudent strategy.
However, months after the introduction of the bivalent vaccine, both the subsequent data accumulation and operational reality prompted regulators to turn to the path of completely "phasing" the original vaccine.
From the data point of view, two mRNA vaccine manufacturers, Pfizer/BioNTech and Moderna, both showed that the use of bivalent Omicron vaccine for primary immunization in young children obtained a better immune response than the original strain of the vaccine. Moderna's basic immunization clinical trials in children aged 6 months to 5 years showed that two doses of BA.1 bivalent vaccine for primary immunization produced similar neutralizing antibodies against the original strain compared with two doses of the original vaccine, while the former had 25-fold higher neutralizing antibodies against the Omicron BA.1 strain [1].
Figure 1. Bivalent mRNA vaccines have shown better immune responses in primary immunoclinical trials in young children[1]
In addition, in the real world, bivalent vaccines as booster shots also increase the effectiveness of protection against mild, severe, and death [1]. Its effectiveness is supported by more solid data today.
With the passage of time, the coexistence of the original vaccine and the bivalent vaccine has become more and more obvious. Clinics and pharmacies responsible for vaccination need to stock different vaccines to cope with different stages of vaccination, which increases the burden of logistics and management. People are also prone to confusion between different vaccines. In the United States, vaccination rates for children and infants are much lower than in other age groups, with only 3.3 percent of children under two years of age and 5.1 percent of children aged 2 to 4 years [3]. In addition to vaccine hesitancy, there is also a factor that cannot be ignored, that is, some parents wonder why they should be vaccinated with the original strain at a time when Omicron is rampant.
Therefore, completely eliminating the original vaccine and fully updating it to a bivalent vaccine not only allows the vaccinated person to get better immune protection, but also makes the vaccination operation simpler and more consistent. At the FDA's advisory committee meeting on Jan. 26, outside experts also unanimously agreed to the proposal.
02 How to get vaccinated in the future: thinking about the near future
The question of what vaccine to administer is solved at the moment, and there is another question ahead: will the new crown vaccine be regularly updated in the future? The Advisory Committee held an open discussion on the matter. "The future" is not out of reach, on the contrary, it is the near future. What the committee needs to discuss is the development and vaccination strategy of the new crown vaccine in the short to medium term. Undoubtedly, this discussion has extremely important reference value for global new crown epidemic prevention.
Although under the dual effects of vaccination and natural infection, the global population generally has a certain immune base for the new crown, we cannot ignore the fact that the new crown virus will exist for a long time, and we cannot ignore the fact that it still causes many severe cases and deaths every day, such as the United States recently still has three or four thousand new crown deaths per week [4]. In addition, immunity from vaccination or infection diminishes over time, and the coronavirus itself continues to evolve. Combined with these factors, it is clear that we need to think about how to use vaccines, the most critical weapon to reduce the severity of the new crown disease, in the future.
The two most common views in the discussion are: "to refer to the model of the flu vaccine" and "The new crown is not the flu". The two views may seem like-for-tat, but there is actually a certain compatibility at the moment.
First of all, the new crown is a respiratory virus like the flu, and it is difficult for the human body to form long-term immune protection, and both viruses are constantly evolving, further increasing the challenge to the immune system. Second, both the new crown and influenza are also high-risk groups - for example, the elderly are more threatened - which means that different groups of people may need to use different degrees of precautions.
Due to these similarities between the two viruses, when we consider the future of the new crown vaccine, we will actively refer to the practice of influenza vaccine, such as the FDA proposed a replacement model for reference to influenza vaccine, starting a new round of new crown vaccination in September every year, and from this point in time, it is necessary to confirm the updated vaccine composition in May-June of that year [5]. Similarly, referring to the flu vaccine, the vast majority of people – such as young people and children who have been vaccinated or infected with the flu – only need one dose each year before the peak of infection, and high-risk groups and young children who have never been vaccinated need to receive more doses, such as completing primary immunization or receiving more booster shots.
However, this proposal has not been universally agreed by the advisory committee because the new crown is not influenza, and the two are not the same.
In response to influenza, a new vaccination strategy is adopted before the peak of infection, provided that influenza does have a significant seasonality, starting in autumn and reaching peak infection in winter. The past epidemic changes of the new crown have been dominated by the replacement of mutant strains, although many scientists speculate that the new crown will also spread seasonally like influenza in the future, but speculation and facts should not be confused. The popularity of Delta and Omicron BA.5 coincides with the summer and autumn of 2021 and 2022. Uncertain seasonality raises doubts about the existence of an appropriate timing for annual vaccination.
In addition to seasonal problems, there are also differences between the new crown and influenza in specific epidemic substrains. Influenza strains vary greatly immunologically, and vaccines targeting one strain have limited cross-protection against another, which is why each year influenza vaccine requires redetermination of composition and annual revaccination [6]. Although there are many variants of the new crown, there is no lack of variants with serious immune escape, but immune escape is limited to infection and mild disease, and in severe disease, cross-protection between different strains can be said to be very good. Specifically, after the emergence of Omicron, the role of the original vaccine in protecting against infection has been greatly reduced, which reflects the significant immune escape of infection and mild disease; At the same time, people who have received the original vaccine still have a significantly lower risk of severe disease after being infected with Omicron than those who have not been vaccinated, and the risk of severe disease after receiving three doses of the original vaccine is lower than that of those who have only received two doses, which shows that in terms of severe protection, Omicron's immune escape is limited.
These differences between the new crown and influenza raise two questions: first, whether it is necessary to constantly update the composition of vaccines; Second, whether it is necessary for most people to be vaccinated every year (regardless of whether the composition is updated or not).
For example, Moderna BA.1 bivalent vaccine has been randomized controlled clinical trials of the original vaccine and booster dose in the United Kingdom, and compared with people who received only the original vaccine, subjects who received the BA.1 bivalent vaccine had less new crown infection (mild disease), but this difference in infection rate is reflected in the effectiveness of the BA.1 bivalent vaccine compared to the original vaccine booster dose is only 10% [1].
Figure 2. Clinical trials have shown that BA.1 bivalent vaccine is 10% effective compared with the original vaccine with a booster dose [1]
The new vaccine has limited improvement, is it worth updating the vaccine every year? Further, for the vast majority of healthy young people, after vaccination, the risk of severe disease and hospitalization is at a very low level for a long time, is it necessary to vaccinate every year?
For example, since April 2022, COVID hospitalization rates in older Americans, especially those over 75 years old, have fluctuated significantly with the pandemic, while hospitalizations among young adults have rarely changed [7]. This suggests that different at-risk groups are actually at different risk, raising two major questions about the "one shot every fall" plan: Should older people wait until the fall to get vaccinated? Is it necessary for young people to be vaccinated every year?
Figure 3. Since April 2022, the fluctuation of new crown hospitalization rates in the United States has been concentrated in the elderly[7]
03 How should the new crown vaccine develop in the future?
In fact, the FDA advisory committee meeting on January 26 was not to immediately clarify the future new crown vaccination plan, but to seek the opinions of relevant experts to see what information is needed and what needs further consideration if the future new crown vaccine research and development and vaccination plan is to be determined. This naturally leads people to think about how the new crown vaccine should develop on a longer time scale.
To determine a truly scientific, effective and reasonable new crown vaccination plan, it is necessary to combine the changes in the epidemic and the actual role of vaccines.
From the perspective of epidemic changes, the new crown virus is still a very "new" virus, and whether it will enter the flu-like seasonality in terms of transmission needs further tracking and confirmation. More importantly, we also need to continue to closely track the genome evolution of the virus, and only by timely detection of new mutant strains with major changes in pathogenicity, immune evasion, etc., can we clarify the frequency of vaccine composition renewal and even the frequency of vaccination.
In terms of the role of vaccines, we need to consider what aspects of the actual vaccines are used. The largest and most lasting effects of available vaccines are protection against severe disease and prevention of death. Then, when exploring future vaccine component updates, vaccination regimens, and frequency, we need to look for data to confirm when and in which population the risk of severe disease from vaccine protection has dropped significantly, and vaccination needs to be updated or strengthened.
At the meetings of the Advisory Board, a question that was raised several times was how to best assess the immune protection of vaccines. In updating bivalent mRNA vaccines, scientists have relied primarily on data on the assessment of serum neutralizing antibodies — bivalent vaccines induce more neutralizing antibodies against Omicron, which means a broader immune response for bivalent vaccines. This assessment is scientifically based, but it does not cover the full range of immune responses.
However, neutralizing antibodies are insufficient to explain all vaccine effectiveness, and their contribution may differ for different effects, such as effectiveness in preventing infection versus protection against severe disease [8]. Therefore, the experts of the Advisory Committee generally proposed that a more reasonable vaccine evaluation scheme is needed through a wider range of immunization indicators, such as T-cell immunity, mucosal immunity and other data.
When we have a more comprehensive and rational way to evaluate vaccines, we can also guide the development of better vaccines in the future. From the ideal effectiveness indicators, we hope that the next generation of vaccines will have wider recognition, so that there is no need to worry about emerging mutant strains that will significantly reduce the effectiveness of the vaccine. We also want the vaccine to be more durable, so that high-risk groups do not have to be vaccinated multiple times a year to protect against the risk of repeated outbreaks. If possible, we also hope that vaccines will be more effective in preventing infection and interrupting transmission, so as to reduce the risk of repeated outbreaks and reduce the potential health burden of infected people due to the new crown.
Today's vaccines, including bivalent mRNA vaccines, do not meet these requirements. In the future, it may be necessary to use more conserved regions on the new coronavirus to design vaccines, such as the current mRNA vaccine is based on the full-length S protein, but the S protein is unfortunately the hardest hit area of the Omicron mutation, scientists may want to consider adding other new crown proteins with fewer mutations as antigens, or let the immune response of the vaccine concentrate in those conserved regions with fewer mutations inside the S protein. In addition, as the most effective vaccine at present, the advantages of mRNA vaccines are high serum neutralizing antibody titers, but for longer lasting protection, it may be better to stimulate cellular immunity; For better infection blockade, stronger mucosal immunity may be elicited. These all depend on the government, scientific research institutions, and the pharmaceutical industry to continue to invest in the research and development of new crown vaccines.
While the FDA's advisory committee discussion focused on U.S. vaccination and research and development, it is also relevant for Chinese researchers and even vaccine-related policy makers. Early breakthrough infection studies of Omicron BA.1 have shown lower neutralizing antibodies in breakthrough infections with inactivated vaccines compared with mRNA vaccine recipients [9]. Recent studies have also shown that breakthrough infection with three doses of inactivated vaccine has a lower immune response than breakthrough infection with two doses [10]. Of course, there is a large amount of evidence that inactivated vaccines reduce the risk of severe disease and provide protection for the majority of Singaporeans. Although the peak of new crown infection at the end of last year has temporarily subsided, combined with these studies, we should realize that how to improve the immune base of Chinese people with better vaccines is still a topic we need to think about.
Resources
[1] https://www.fda.gov/media/164810/download
[2] https://www.sciencedirect.com/science/article/pii/S0092867422003889?via%3Dihub
[3] https://www.fda.gov/media/164816/download
[4] https://covid.cdc.gov/covid-data-tracker/#trends_weeklydeaths_select_00
[5] https://www.fda.gov/media/164807/download
[6] https://www.cdc.gov/flu/about/viruses/types.htm
[7] https://www.fda.gov/media/164814/download
[8] https://www.fda.gov/media/164809/download
[9] https://www.nature.com/articles/s41421-022-00501-3
[10] https://www.nature.com/articles/s41422-023-00781-8
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