Personal views do not represent any organization or unit
Recently, due to the outbreak of the domestic epidemic, everyone's attention has focused on the symptoms of the new crown and antiviral drugs, and the attention to vaccines has been much lower (there are many fewer people asking which vaccine to receive in the background, in fact, many people's questions were also written in the vaccination Q&A a month ago). This decline in attention is not difficult to understand: when it first opened, many people thought about getting vaccinated while they were not infected, and now many people may have been vaccinated with live Omicron virus whether they want to or not, who cares about vaccines?
1. Vaccines remain critical
In fact, vaccines will remain a key pillar of preparedness for a long time to come. The much-anticipated Paxlovid is the best new crown antiviral drug at the moment, which can reduce the risk of severe hospitalization in unvaccinated high-risk people by about 90%. But if we look at the new crown vaccine, even if it is an inactivated vaccine with low effectiveness, three shots can reduce the risk of severe disease in Omicron by more than 95% [Hong Kong data, 1]:
Vaccines are also available to a wider range of people, and everyone but a very small number of people who are allergic to the components of the vaccine can benefit from vaccination. Even those who are allergic to a certain vaccine, because there are many types of new crown vaccines, another vaccination is over.
In contrast, Paxlovid liver kidney function problems can not be used, drug conflicts will also make some people unable to use. Paxlovid can switch to molnupiravir, but the latter is much less effective and has its own potential safety problems.
Some people will have less effective vaccines, such as the elderly and immunosuppressed people, but this can often be remedied by getting an extra shot (booster shot). The effectiveness of antiviral drugs is useless, evidence that eating more can be improved, and people who are not suitable can not eat more.
More critically, the effectiveness of vaccines against severe disease is long-lasting – perhaps not as long as we would like, but not even months. Antiviral drugs are small molecule drugs, and the drugs are quickly metabolized by the body after stopping the drug, and the antiviral effect disappears.
From an economic point of view, the purchase price of the world's most expensive mRNA new crown vaccine is only forty or fifty US dollars, even if the commercial price increases in the future, it will probably rise to 120-130 US dollars a shot. But now Paxlovid in developed countries in Europe and the United States purchase price of more than $500.
It can be seen that vaccines are the tool with the lowest economic cost, the widest scope and the best safety to reduce the severity of new crown diseases. Many people in China have recently been infected, and the risk of secondary infection in the short term is low, and the risk of severe illness caused by secondary infection is also low, but over time, the protection brought by these natural infections will decrease. We are also uncertain how long the protection against this breakthrough infection lasts at a low immune base (China is dominated by inactivated vaccines with low immunogenicity). Therefore, we still need to think about the next shot of the vaccine and need to focus on the future of the new crown vaccine.
2. Are bivalent mRNA vaccines good enough?
Recently, several scholars in the United States have published articles discussing the role of the current bivalent mRNA vaccine, and many thoughts are worth learning.
Ideas like Paul Offit (U Penn) and Eric Topol (Scripps) have very different views. In January, NEJM published Offit's insight article Bivalent Covid-19 Vaccines — A Cautionary Tale [2]. Offit traced the FDA's review of the bivalent vaccine, noting that in his opinion, the clinical trial immunological data of the BA.1 bivalent vaccine at that time was relatively average - the neutralizing antibody titer against BA.1 was only 1.5-1.75 times that of the original vaccine. At that time, BA.1 was extinct, so the FDA made the decision to go directly to BA.5 bivalent.
But in October, some immunological studies found that BA.5 divalent was no better than the original vaccine. CDC tracking in November showed that 2-3 months after receiving a monovalent mRNA booster (the original vaccine), the bivalent booster dose increased the effectiveness of protection against symptomatic infection by only 28-31%, and the interval was extended to 8 months, and the increased effectiveness was only 43-56%. By December, BA.5 accounted for only 25% of infections in the United States and had been replaced by other strains (e.g., BQ.1, XBB).
In Offit's view, this shows the limited advantages offered by bivalent vaccines today. Although the new coronavirus mutates quickly, it has not evolved to break through the protection against severe disease brought by the original strain of vaccine and past infections. This results in limited improvement over the original bivalent vaccine from the updated bivalent vaccine. At the same time, he believes that because the effectiveness of the booster shot in preventing symptomatic infection is not high, for a respiratory virus with a short incubation period, preventing severe disease is the possible goal, so the booster shot should be aimed at the elderly, immunosuppressed people and people with multiple underlying diseases. For the majority of young people, it makes no sense to use constantly changing booster shots to eliminate the new crown infection that will replace the mainstream virus strain in a few months.
Topol wrote that there is a lot of evidence that the bivalent vaccine booster outperforms ([3]). Evidence included that induced BA.5 and XBB neutralizing antibodies were higher than those of the original vaccine. Real-world studies also show that older people who receive the bivalent vaccine have a lower risk of hospitalization – the benefits for young people may be lower, but in principle, there is no reason to think that young people will be worse off with the bivalent vaccine (after all, young people will also have an immune response).
Topol feels that Offit has been crooked about booster shots, and it is clear that the bivalent vaccine has a good protection against severe disease, and to question the role of the bivalent vaccine is a continuation of this chirping.
3. Same path
Offit and Topol's views on bivalent vaccines, who is right and who is wrong? In my opinion, both people have a point, just a different starting point.
Offit wants to say that the bivalent vaccine and the original vaccine ratio (only refers to the two foreign mRNA vaccines), the advantage is not outstanding. Topol's focus on the bivalent vaccine still works. The data they see is actually the same, and there are many essentially the same views.
For example, both agree that it makes more sense to target people at higher risk of severe disease (the elderly, etc.). Like Topol's many articles on the anti-severe effect of bivalent vaccines, they are all studies in the elderly. Topol also admitted that the current bivalent vaccine is not perfect and cannot effectively prevent transmission and infection. And this is the key to Offit's belief that young people continue to get booster shots - these people's risk of severe disease is already very low after several vaccinations, and then go for booster shots, whether bivalent or not, the actual benefits are only short-term infection prevention effects. Doing so is partly a waste of medical resources and bad public policy.
The biggest difference between the two views is in the interpretation of the neutralizing antibody titers, Offit feels that the divalent neutralizing antibody titer is one or two times higher, and it is difficult to explain the difference in substantive effectiveness; The starting point of Topol is that more is better than nothing, and more accurately the neutralizing antibodies that are bivalent mean that the immune response is broader. However, Topol also acknowledges that these improvements are not a seismic qualitative change, which is actually the same as Offit.
Taken together, both experts see that it is extremely important to enhance protection against severe disease in high-risk groups, but at the same time, they also see that the increase in neutralizing antibodies brought by the current second-generation mRNA vaccine is not enough to change the weakness of the vaccine in infection prevention. In addition, the new crown is still evolving, which brings some uncertainty about how long current vaccines, including the non-revolutionary bivalent vaccine, will protect against severe disease in the future. What if a mutant strain emerges that also has immune escape for severe disease protection?
4. How should the bivalent vaccine be used?
Therefore, the current mRNA bivalent vaccine is an excellent and useful vaccine, but not excellent enough. This also raises Offit's objection to the use of bivalent vaccines: For whom is such a useful but far from perfect vaccine necessary? This is something that must be taken into account when developing vaccination policies. If you look at the bivalent vaccination rate in the United States [4]:
To date, fewer than 50 million people have been vaccinated against bivalent vaccines, and less than 40% of people over 65 years of age have been vaccinated. The U.S. purchased 105 million doses of the Pfizer/BioNTech bivalent vaccine, with 66 million in the Moderna version. Such a low vaccination rate corresponding to such a high procurement volume is undoubtedly a huge waste.
More importantly, the current new crown hospitalizations are highly concentrated in the elderly, such as the recent new new crown hospitalizations for people over 70 years old in the United States have been close to the Delta peak, while young people have almost no fluctuations [5]:
Several studies have shown that bivalent vaccines can significantly reduce the risk of hospitalization, and if bivalent vaccination rates in older people were higher, the increase in hospitalization rates would not be as significant. From a public policy perspective, it may be better to focus on persuading older people to accept bivalent vaccines rather than universal adoption. This may be one of the reasons Offit has a negative attitude towards promoting booster shots to young people. However, he also raised another soulful question: Can the original vaccine also have the same or similar effect?
Yes, there are multiple studies that show that older people who receive the bivalent vaccine have lower rates of hospitalization, but this is not the ratio of a bivalent booster shot to a booster shot of the original vaccine, but a ratio of a bivalent booster shot to no shot. Considering that the bivalent vaccine did not increase the antibody titer much compared to the original vaccine, and the association between antibody titer and protection against severe disease was weaker than that of infection prevention, and the original vaccine also restored the anti-severe effect with a booster shot, it is really difficult to say how bad it will be with the original mRNA vaccine.
But I personally think it is still necessary to note that the higher antibody titers brought by bivalent may mean that the time to protect against severe disease will be longer. And realistically speaking, sampling the original vaccine for booster shots is likely to be less willing to be vaccinated, including the elderly.
5. What will the future of vaccines look like?
Obviously, even with the best new crown vaccine at the moment, the shortcomings of bivalent mRNA vaccines still limit our epidemic prevention, such as using vaccination to suppress the spread of the new crown. That's why both Offit and Topol have suggested that better vaccines are needed in the future. On this topic, Peter Marks, head of the FDA's Center for Biologics Evaluation and Research (CBER, responsible for vaccine approval), co-authored, and the opinion article "Urgent Need for Next-Generation COVID-19 Vaccines" published in JAMA in December is worth considering [6].
From the perspective of the shortcomings of the current vaccine, the biggest problem is that in the face of the evolving new crown virus - three or four months may change a mainstream mutant strain, there is uncertainty about the persistence of vaccine protection against severe disease, especially in high-risk groups. When the bivalent vaccine was launched, the inference put forward by the relevant pharmaceutical companies was that the bivalent vaccine had a higher immune response and had little effect on preventing severe disease for 6 months. This assumption is not unreasonable, but the question is whether such long-term protection can be achieved in high-risk groups? And is 6 months enough? The increase in new crown infections is often related to the emergence of new mainstream virus strains, and may not be able to assume that a shot before entering the winter can solve the problem after half a year of protection like influenza.
In response, Marks et al. proposed the need for a true new generation of new crown vaccines, which should refer to the standard of broad-spectrum influenza vaccines: maintain at least 75% effectiveness against disease for one year. In addition to preventing disease and severe disease, if transmission can be reduced by 40-60%, it will be more beneficial to limit the new crown epidemic.
To achieve the above goals, including the minimum target of 75% disease prevention for one year, it is highly unlikely that it can be achieved by simply changing the antigen sequence like a bivalent mRNA vaccine. It also cannot be verified by the immune bridging used in previous bivalent mRNA vaccines when they were marketed. Marks et al. also point to some of today's attempts at inhaled vaccines, again pointing out that there is not enough evidence to show how much practical change this existing vaccine can bring about by simply changing the delivery method.
What the next generation of new crown vaccines needs to do may be to rethink the vaccine design, consider which parts of the new crown are less affected by mutations and have sufficient immunogenicity. Even more use of cellular immunity that is more difficult to break through by antigen mutations can be considered. After the restart of vaccine design, the verification of the actual effect of the vaccine also needs to be restarted. Based on the difference in antibody titers for a short period of time after vaccination, it is difficult to predict how durable the actual protection will be.
In short, Marks et al. believe that the real next-generation new crown vaccine needs to reintegrate the current vaccine design and production experience, and try to incorporate the knowledge and technology that has not been adopted by the current vaccine.
These reflections are also of great reference value for China. After experiencing the peak of the first wave of Omicron, China may enter a stable period of the epidemic in the next few months, and infections, hospitalizations, etc. will fall back to a low level. From global experience, the immune base formed after the peak of this epidemic will fall back in a few months, when high-risk groups will face the test. While dealing with the current peak of severe disease, we must not forget that it remains crucial to identify more effective and equitable vaccination regimens in the future within a limited time.
Resources
1.https://doi.org/10.1016/S1473-3099(22)00345-0
2.DOI: 10.1056/NEJMp2215780
3.https://erictopol.substack.com/p/the-bivalent-vaccine-booster-outperforms
4.https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-people-booster-percent-pop5
5.https://covid.cdc.gov/covid-data-tracker/#new-hospital-admissions
6.https://jamanetwork.com/journals/jama/fullarticle/2799600