The United States is phasing out the original strain of the COVID-19 vaccine. Will it be administered annually like the flu vaccine?

How to use better vaccines to improve the immune foundation of our people is still an issue we need to think about.

Written by Zhou Yebin (PhD, University of Alabama at Birmingham)

On January 26, 2023, the U.S. Food and Drug Administration (FDA) held a meeting of the Vaccines and Biologics Advisory Committee. During the meeting, external independent scientists convened by the FDA voted in favor of eliminating the monovalent vaccine based on the original virus strain and completely switching to a bivalent vaccine containing the Omicron antigen component. In addition, the meeting also discussed the future update process of the new crown vaccine and the future development direction of the vaccine. So why did the U.S. government change the vaccine, and what information did this meeting reveal about the future development of the new crown vaccine?

01 "Eliminating" the original vaccine: solving the current problem

In the fall of 2022, the COVID-19 mRNA vaccine was updated for the first time, with a bivalent vaccine launched as a new booster shot. This bivalent vaccine includes half a dose of the original strain vaccine and the other half an updated vaccine containing the Omicron spike protein sequence. There are two versions of the specific Omicron sequence. The United States only uses a bivalent vaccine based on BA.4/5, while other parts of the world also have a bivalent vaccine based on BA.1.

It is worth noting that after the bivalent vaccine was launched, it was only used for booster shots. A person who had not been vaccinated still had to use the original vaccine for basic immunization. Why didn't the bivalent vaccine completely replace the original vaccine? There were multiple considerations.

First, in terms of basic immunization, the original vaccine has a lot of data to support its effectiveness and safety, while the main data relied on when the bivalent vaccine was launched came from the booster shot test of the BA.1 version in humans and the booster shot test of the BA.4/5 version in animal models. To directly promote it to basic immunization, the data is not perfect.

Secondly, in the booster clinical trial at the time, the titer of neutralizing antibodies against BA.1 substrain induced by the BA.1 version of the bivalent vaccine was only about 1.75 times that of the original vaccine [1]. The limited improvement means that the bivalent vaccine is not a "revolutionary" improvement, which means that there is no need to rush to completely replace the original vaccine with the bivalent vaccine.

Thirdly, some animal experiments have shown that the monovalent Omicron vaccine is not much better than the original vaccine in terms of immune response and protection against the Omicron virus strain (animals are infected with the virus after vaccination to test the protective effect) [2]. This has also made regulatory agencies and the medical community more cautious about switching to a full bivalent vaccine.

Based on these data at the time, WHO, FDA, etc. chose to use Omicron bivalent vaccine as a booster shot without changing the composition of the basic immunization vaccine. This is a more prudent strategy.

However, a few months after the launch of the bivalent vaccine, both the subsequent data accumulation and operational realities prompted regulators to turn to the path of completely "eliminating" the original vaccine.

From the data, both mRNA vaccine manufacturers Pfizer/BioNTech and Moderna have shown that the use of the bivalent Omicron vaccine as a basic immunization in young children has a better immune response than the original strain vaccine. Moderna's clinical trial of basic immunization in children aged 6 months to 5 years showed that two doses of the bivalent BA.1 vaccine as a basic immunization produced similar neutralizing antibodies against the original strain as two doses of the original strain vaccine, while the former had 25 times higher neutralizing antibodies against the Omicron BA.1 strain [1].

Figure 1. Bivalent mRNA vaccine showed better immune response in clinical trials for primary immunization of young children [1]

In addition, in the real world, the bivalent vaccine as a booster shot also increases the effectiveness of protection against mild, severe, and death[1]. Its effectiveness is now supported by more solid data.

As time goes by, the problems caused by the coexistence of the original vaccine and the bivalent vaccine have become more and more obvious. Clinics and pharmacies responsible for vaccination need to stock different vaccines to cope with recipients at different stages, which increases the burden of logistics and management. People are also easily confused by different vaccines. In the United States, the vaccination rate of children and infants is much lower than that of other age groups. The basic immunization rate for children under two years old is only 3.3%, and that for children aged 2-4 is only 5.1% [3]. In addition to vaccine hesitancy, another factor that cannot be ignored is that some parents wonder why they should vaccinate with the original vaccine when Omicron is rampant.

Therefore, completely eliminating the original vaccine and fully updating it to a bivalent vaccine will not only provide better immune protection for the vaccine recipients, but also make the vaccination process simpler and more consistent. At the FDA's advisory committee meeting on January 26, external experts also unanimously agreed to this proposal.

02 How to vaccinate in the future: Thinking about the near future

The question of which vaccine to take has been solved, but there is another question: Will the COVID-19 vaccine be regularly updated in the future? The Advisory Committee held an open discussion on this. "In the future" is not far away, on the contrary, it is the near future. What the committee needs to discuss is the COVID-19 vaccine development and vaccination strategy in the short and medium term. Undoubtedly, this discussion has extremely important reference value for the global COVID-19 prevention.

Although the global population has a certain immune basis to COVID-19 due to the dual effects of vaccination and natural infection, we cannot ignore the fact that COVID-19 will exist for a long time and that it still causes severe illness and death in many people every day. For example, the United States has recently seen three to four thousand COVID-19 deaths per week[4]. In addition, as time goes by, the immunity formed by vaccination or infection will diminish, and the COVID-19 itself is still evolving. Taking all these factors into consideration, we obviously need to think about how to use vaccines, the most critical weapon to reduce the severity of COVID-19, in the future.

The two most common viewpoints in the discussion are: ① "We should refer to the model of influenza vaccines" and ② "COVID-19 is not influenza." These two viewpoints seem to be diametrically opposed, but they are actually compatible to a certain extent at the moment.

First, COVID-19, like influenza, is a respiratory virus, and it is difficult for the human body to form long-term immune protection. Both viruses are constantly evolving, further increasing the challenge to the immune system. Second, both COVID-19 and influenza also have high-risk groups - for example, the elderly are more threatened - which means that different groups may need to adopt different levels of prevention measures.

Because of these similarities between the two viruses, when we consider the future of the COVID-19 vaccine, we will actively refer to the practice of influenza vaccines. For example, the FDA has proposed a reference to the replacement model of influenza vaccines, starting a new round of COVID-19 vaccinations in September each year, and working backwards from this point in time, the updated vaccine composition must be confirmed in May-June of the same year[5]. Similarly, referring to the influenza vaccine, most people - such as young people and children who have been vaccinated or infected with influenza - only need to receive one shot before the peak of infection each year, while high-risk groups and young children who have never been vaccinated need to receive more shots, such as completing basic immunization or receiving more booster shots.

However, this proposal was not generally accepted by the advisory committee because: COVID-19 is not influenza, the two are not the same.

In response to influenza, the strategy of launching a new vaccination before the peak of infection is adopted, on the premise that influenza does have obvious seasonality, starting in autumn every year and reaching the peak of infection in winter. The changes in the COVID-19 epidemic in the past have been dominated by the replacement of mutant strains . Although many scientists speculate that COVID-19 will spread seasonally like influenza in the future, speculation should not be confused with facts . For example, the epidemics of Delta and Omicron BA.5 happened to be in the summer and autumn of 2021 and 2022. The uncertainty of seasonality makes people doubt whether there is an appropriate annual vaccination time.

In addition to seasonality, there are also differences between COVID-19 and influenza in terms of specific substrains. Different strains of influenza differ greatly in immunology, and vaccines against one strain have limited cross-protection against another strain. This is why the composition of influenza vaccines needs to be re-determined and re-vaccinated every year [6]. Although there are many variants of COVID-19, there are also variants with severe immune escape, but immune escape is limited to infection and mild symptoms. In terms of severe illness, cross-protection between different strains can be said to be very good. Specifically, after the emergence of Omicron, the effectiveness of the original vaccine in protecting against infection has dropped significantly, which reflects the significant immune escape in infection and mild illness; at the same time, the risk of severe illness after infection with Omicron is still significantly lower for people who have been vaccinated with the original vaccine than for those who have not been vaccinated. The risk of severe illness for those who have received three doses of the original vaccine is lower than that for those who have only received two doses, which shows that in terms of severe illness protection, Omicron's immune escape is limited.

These differences between COVID-19 and influenza bring up two questions: first, is it necessary to constantly update the composition of the vaccine? Second, is it necessary for most people to get vaccinated every year (regardless of whether the composition is updated).

For example, Moderna's BA.1 bivalent vaccine was tested in a randomized controlled clinical trial in the UK with an original vaccine and a booster shot. Compared with those who only received the original vaccine, those who received the BA.1 bivalent vaccine had fewer COVID-19 infections (mild symptoms). However, this difference in infection rates is reflected in the fact that the effectiveness of the BA.1 bivalent vaccine relative to the original vaccine booster shot is only 10%[1].

Figure 2. Clinical trials show that the effectiveness of the BA.1 bivalent vaccine as a booster shot is 10% higher than that of the original vaccine [1]

The new vaccine has limited effect, so is it worth updating it every year? Furthermore, for the vast majority of healthy young people, the risk of severe illness and hospitalization remains at a very low level after vaccination. Is it necessary to vaccinate every year?

For example, since April 2022, the COVID-19 hospitalization rate for older Americans, especially those over 75 years old, has fluctuated significantly with the epidemic, while the hospitalization rate for young people has changed little[7]. This shows that different risk groups are actually threatened differently, which raises two major questions about the plan of "getting vaccinated once a year in the fall": ① Should the elderly wait until the fall to get vaccinated? ② Is it necessary for young people to get vaccinated every year?

Figure 3. Fluctuations in COVID-19 hospitalization rates in the United States since April 2022 are concentrated among the elderly [7]

03 How should the new coronavirus vaccine develop in the future?

In fact, the FDA advisory committee meeting on January 26 was not to immediately clarify the future COVID-19 vaccination plan, but to solicit the opinions of relevant experts to see what information is needed and what areas need further consideration in order to determine the future COVID-19 vaccine development and vaccination plan. This naturally leads people to think about how the COVID-19 vaccine should develop in the longer term.

To determine a truly scientific, effective and reasonable COVID-19 vaccination plan, it is necessary to combine the changes in the epidemic and the actual effects of the vaccine.

From the perspective of the epidemic situation, the new coronavirus is still a very "new" virus. Whether it will enter the seasonality of influenza in terms of transmission needs further tracking and confirmation. More importantly, we need to continue to closely track the evolution of the virus genome. Only by timely discovering new mutants with major changes in pathogenicity, immune escape, etc. can we clarify the update frequency of vaccine composition and even the frequency of vaccination.

As for the role of vaccines, we need to consider what aspects of vaccines are actually used. The biggest and most lasting role of existing vaccines is protection against severe illness and prevention of death. So when exploring future updates to vaccine ingredients and vaccination plans and frequencies, we need to look for data to confirm when and in which population the risk of severe illness from vaccine protection has dropped significantly, and that updated or enhanced vaccinations are needed.

At the advisory committee meeting, a question that was mentioned many times was how to fully evaluate the immune protection of the vaccine. In the process of updating the bivalent mRNA vaccine, scientists mainly relied on the evaluation of serum neutralizing antibodies - the bivalent vaccine induced more neutralizing antibodies against Omicron, which means that the immune response of the bivalent vaccine is broader. This evaluation method has scientific basis, but it cannot cover all immune responses.

However, neutralizing antibodies are not sufficient to explain all vaccine effectiveness, and the contribution of neutralizing antibodies to different effectiveness, such as effectiveness in preventing infection and effectiveness in protecting against severe illness, may also be different [8]. Therefore, the experts on the advisory committee generally proposed that a more reasonable vaccine evaluation scheme should be found through a wider range of immune indicators, such as data on T cell immunity and mucosal immunity.

And when we have mastered a more comprehensive and reasonable method to evaluate vaccines, it can also guide the development of better vaccines in the future. From the perspective of ideal effectiveness indicators, we hope that the next generation of vaccines will have a wider recognition, so that there is no need to worry about the emergence of new mutants that will significantly reduce the effectiveness of the vaccine. We also hope that the vaccine will have better durability, so as to prevent high-risk groups from having to be vaccinated multiple times within a year in order to prevent the risk of recurrence of the epidemic. If possible, we also hope that the vaccine will be more effective in preventing infection and blocking transmission, so as to reduce the risk of recurrence of the epidemic and reduce the potential health burden of infected people caused by the new crown.

Today's vaccines, including bivalent mRNA vaccines, cannot meet the above requirements. In the future, it may be necessary to use more conservative regions of the new coronavirus to design vaccines. For example, the current mRNA vaccine is based on the full-length S protein, but the S protein happens to be the hardest hit area of ​​​​Omicron mutation. Scientists may have to consider adding other new coronavirus proteins with fewer mutations as antigens, or let the vaccine's immune response focus on those conservative regions with fewer mutations inside the S protein. In addition, as the most effective vaccine at present, the advantage of mRNA vaccines is reflected in the high titer of serum neutralizing antibodies, but if you want more lasting protection, you may need to better stimulate cellular immunity; if you want to have a better blocking effect on infection, you may need to stimulate stronger mucosal immunity. All of this depends on the continued investment of the government, scientific research institutions, and the pharmaceutical industry in the research and development of new coronavirus vaccines.

Although the FDA advisory committee's discussion was aimed at vaccination and research and development in the United States, its content is also worth learning from for Chinese researchers and even vaccine-related policy makers. Early breakthrough infection studies of Omicron BA.1 showed that the neutralizing antibodies of inactivated vaccine breakthrough infection recipients were lower than those of mRNA vaccine recipients [9]. Recent studies have also shown that the intensity of immune response to breakthrough infection after three doses of inactivated vaccine is lower than that of breakthrough infection after two doses of vaccine [10]. Of course, a large amount of evidence shows that inactivated vaccines reduce the risk of severe illness and provide protection for the majority of Chinese people. Although the peak of new crown infections at the end of last year has temporarily subsided, combined with these studies, we should realize that how to use better vaccines to improve the immune foundation of Chinese people is still an issue we need to think about.

References

[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

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Produced by: Science Popularization China

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