Not only in Europe and the United States began to implement the enhanced injection, but also the domestic high-risk personnel also began to recommend additional enhancement injection | after six months of inactivated vaccine Image source: pixabay.com
Introduction
Faced with the coronavirus, which has been known for less than two years and the rapidly changing epidemic, many times our decisions have to be based on relatively incomplete information, and the same is true for the enhancement needle. This prompts us to refine the relevant research as soon as possible, supplement the completeness of the relevant data, and also remind ourselves that we should be cautious in making decisions on the lack of information.
Written by | Zhou Yebin
Responsible editor| Chen Xiaoxue
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Many developed countries in Europe and the United States have begun to formulate and even implement enhanced vaccination plans for the new crown vaccine for the general population. But for the new crown vaccine, which only began to be launched at the beginning of this year, it will be "enhanced" after just a few months, and the scientificity and necessity of this is still a very controversial topic.
The U.S. Food and Drug Administration (FDA) meeting on Pfizer/BioNTech vaccine boosters on September 17 may be the first time to openly and transparently debate the significance of boosters and the scientific nature of related policies.
Over the course of more than eight hours of analytical discussions, the U.S. Centers for Disease Control and Prevention (CDC), the FDA, and Pfizer/BioNTech each listed the data, and even Israel, the first to administer the augmentation injection, sent health officials and researchers to provide the latest data from the country. Finally, the expert meeting rejected the Pfizer/BioNTech's proposal for a universal booster needle by an absolute majority, instead recommending the provision of booster needles to the elderly over 65 years of age and other high-risk groups.
This proposal has now also been officially approved by the FDA and recommended by the CDC. The meeting and the CDC recommendation of the enhanced needle meeting on September 22-23 provided a large number of existing data and decision-making basis discussions on the enhancement needle, which not only allowed many people concerned about the enhancement needle to understand the current situation of the enhanced needle, but also worthy of reference by all the management departments that formulated the enhanced needle policy and even the general epidemic prevention policy.
Principle: Is it a reinforcement needle or a third needle?
In various reports, one of the benefits of the booster needle that is often mentioned is that it can greatly increase the antibody, which is also the key data used by pharmaceutical companies such as Pfizer/BioNTech to apply for the marketing of the booster needle. A significant increase in antibodies was detected after inoculation of the booster needle, reflecting the immune response excited by the booster needle. But the immune response is far more than the antibody part, and the scientific principle of the booster needle is not limited to the antibody increase this link.
On September 17, the US FDA expert meeting and the CDC's many discussion meetings on enhancement needles mentioned that from the principle of consideration, if the new crown mRNA vaccinator is given a third dose, is it a matter of changing the initial vaccination procedure from two to three injections, or is it an enhancement needle outside the initial vaccination?
It's all the third shot, is there a difference between the initial vaccination procedure?
In fact, the number of vaccinations for different vaccines is itself different. For example, the herpes zoster vaccine is two shots, while the hepatitis B vaccine is three shots. This difference in the number of needles is based on the perfection of the immune response.
For vaccines, the first shot stimulates an initial immune response that involves B cells being activated to produce specific antibodies against the antigens introduced by the vaccine, while forming some memory B cells. These memory cells do not produce antibodies, but retain memories of antigens, and when they encounter the same antigen again, they can quickly replicate and differentiate into a large number of B cells that can make antibodies.
In general, the intensity of the immune response stimulated by the first dose of vaccine is not large, which is manifested by the production of few antibodies and the formation of memory cells is limited. When a period of time after the first dose of vaccination - at least until the first dose of induced immune response declines, by giving the second dose of vaccine, the body's immune system can produce a stronger immune response, the so-called enhancement, in this process, there will be a large number of antibodies produced, and there will be more binding ability or recognition of more diverse antibodies, while memory cells and the like will be further improved, some B cells can also differentiate into plasma cells. Plasma cells are very long-lived, migrate to the bone marrow and produce antibodies over time, allowing the body to gain long-term immune protection.
Because of this pattern of immune response during vaccination, most vaccines require two shots, and there must be a certain interval between the two doses. However, not all vaccines can get the most complete immune protection after two injections, which is why many vaccines such as hepatitis B vaccine need to be given a third dose to complete vaccination.
Back to the COVID-19 vaccine, as a newly developed vaccine, such as the Pfizer/BioNTech mRNA vaccine, it is now known that two injections can obtain very good immune protection. But is the two-shot immune response the limit of the human immune system?
This is unknown.
If the immune response induced by the first two injections is already the limit of the human immune response that such vaccines can stimulate, then the third injection only stimulates immune memory and produces a large number of antibodies again, but including memory cells, the degree of diversification of antibodies, etc. will not be improved. The human body does not continuously mass-produce antibodies that are not used, so the high antibodies excited by the third needle will also decrease over time. In other words, the effect of this booster needle is only to temporarily increase the antibody titer in the body.
If the results of the first two doses of mRNA vaccine are not the limit of the body's immune response, then the introduction of a third dose may be like the third dose of the hepatitis B vaccine, which can further improve immune protection. This may have a variety of manifestations, such as stimulating the formation of more memory cells, so that the next time the virus encounters a faster and stronger immune response, better protection; or the production of more "mature" antibodies, they are more able to bind to the virus or more diversified recognition, enhance the protection against mutations; or the formation of more long-acting plasma cells, so that the decline curve of antibodies slows down, so that the body is protected for a longer period of time.
If the third dose of mRNA vaccine can indeed play a role in further refining the immune response, or even infer that the initial vaccination process of the new crown vaccine should be three shots, then the vaccine should be designed as a three-shot vaccine instead of a two-shot vaccine.
Unfortunately, there is not enough data to point to whether the booster needle only temporarily increases the antibody titer or can perfect the overall immune response. Pfizer/BioNTech provided antibody titers at the FDA expert meeting only one month after the third dose. Although this titer is three times the peak after the second dose, it is impossible to distinguish whether the third shot perfects the overall immune response of the vaccinated person or pulls up the antibody shortly.
Recent studies of mRNA vaccines have shown that antibody diversity, memory cells, and cellular immunity seem to have reached a limit after the second injection [1,2]. If these studies are universal, the significance of the booster needle will be limited to the short-term increase in antibodies. However, these studies are still in the early stages, and the results may vary from population to population, such as the elderly may have a weak immune response, even if the first two injections in the general population can reach the limit of the immune response, but not necessarily for the elderly or people with underlying diseases.
But in any case, the booster needle still needs more sophisticated research, not only limited to the antibody titer of a time intercept point, to clarify the role of the booster needle.
Timing: Is the reinforcement needle needed now?
The scientific principles of the reinforcement needle also affect another important question: when is the reinforcement needle needed, or is it needed now?
If the booster needle only briefly increases the antibody, the timing of use will depend on when the antibody needs to be increased.
Now many enhancement needle plans to 6 months as a boundary, the main basis of this division is that when the antibody titer of some vaccines is tracked, it is found that after 6 months of vaccination, the antibody ratio in vivo has dropped a lot at the peak, such as Moderna recently published 6 months of neutralizing antibody tracking data in Science [3], and found that after half a year, the serum of the vaccinator can still neutralize multiple mutant strains, including Delta, but the titer of the neutralizing antibody has dropped significantly compared with the time of vaccination. That is, the same number of viruses in the experiment require the use of more serum.
There are still neutralizing antibodies in the body after 6 months of Moderna vaccination but the titer is significantly reduced from the peak | Image source[3]
Studies have shown that higher neutralizing antibody titers correspond to better COVID-19 vaccine effectiveness. Purely from the perspective of increasing antibodies in vivo, it seems that there is no problem in increasing antibody titers by taking booster injections after half a year because of the decline in antibodies in vivo. But this approach lacks the most fundamental basis, which is that scientists have not yet defined a lower limit of antibodies necessary for vaccine protection. That is to say, although the antibody titer did drop sharply after half a year (this is also expected, because in the absence of a virus, the human body does not have to mass-produce an unused antibody), it cannot be said that the protective effect of the vaccine has declined significantly at this time.
Again from The Modela analysis, which, according to its Phase III clinical trial, found that even in people who could not detect neutralizing antibodies after vaccination, the vaccine efficacy was still 50% in the next three months, while those with neutralizing antibody titers of 100 and 1000 neutralizing antibodies were 90% and 96% effective, respectively [4]. So not only to see the decline in neutralizing antibody titer can not be clear whether the vaccine is ineffective need to be enhanced, even if the booster needle greatly improves the antibody, how much of the protective effect of the vaccine can be corresponded to the increase in the protective effect of the vaccine also needs to be examined, after all, the 10-fold neutralizing antibody difference for the first two doses of Moderna only brought a 6% difference in effectiveness, like Pfizer /BioNTech's booster needle to improve the antibody titer to the peak of the second shot 3 times, the change in vaccine effectiveness is still unknown, It is likely that it will not change as much as the antibody titer.
In addition, if the increase in antibodies is used as a benchmark, the antibodies will decline after the peak after the injection, and a natural question is whether the reinforcement injection will be frequently used to maintain the antibody at a high level in the future. At the FDA expert meeting, some U.S. experts asked Israeli health officials whether they planned to give the booster injection later if the increase in effectiveness was only based on temporary antibody enhancement. Previously, Israeli officials said that a fourth injection needed to be prepared [5], but Israeli health officials at the expert meeting said that they had no intention of doing so.
If the third shot is to perfect the immune response, then the question should be how long between the third shots can perfect the immune response. How long is this time, is it 6 months? It is not clear now, theoretically the longer the interval, the better the enhancement of this perfect immune protection. However, if it is proved that a short interval can also be done, then it is possible to complete three injections of vaccination at shorter intervals and improve the vaccination effect as soon as possible.
Some scientists have also proposed another idea, that is, whether to improve the immune protection of the vaccine by changing the interval between the first two doses of the vaccine. Some people at the FDA expert meeting suggested that the vaccination procedure of the new crown vaccine is now very aggressive, such as Pfizer/BioNTech is two injections of three weeks apart, is it because such a short interval leads to insufficient perfection of the immune response, resulting in insufficient maintenance of vaccine effectiveness? If the interval between the two injections is extended, can the immune protection be longer and avoid the need for booster needles in the future?
However, extending the interval between the two injections will make the vaccinated person in a semi-vaccinated state for a longer period of time, without sufficient protection, which is not necessarily better in terms of risk and return, and is even less meaningful for people who have been vaccinated, because those who have been vaccinated cannot change the interval between the previous two injections.
In conclusion, in scientific principles, the main evidence for a third or enhanced needle now is that antibodies can be greatly increased. But in addition to antibodies, whether the overall immune response is perfect, how often the interval between third shots is better, how much actual effectiveness it translates into, and how long it can be maintained are unknown.
In this case, another way to explore the need to enhance the need for injections is based on the actual changes in the effectiveness of vaccines, especially the effectiveness of intensive care protection. Absolute prevention of infection itself is a very high requirement, especially now the vaccine to deal with the very strong spread of Delta mutation strain, many countries in Europe and the United States infection rate is very high, equivalent to the vaccine patient for a long time in a high virus volume environment, vaccination rate for various reasons in many countries is not ideal, these factors are superimposed, expect vaccines to completely block infection or transmission is not realistic. Therefore, maintaining the vaccine's protection against severe diseases is a more reasonable and critical goal.
Various studies have shown that the mRNA vaccine has a certain decline in protecting against infections or mild diseases, but the protection against severe diseases remains at a high level. The decrease in protection against mild diseases may have both the effect of vaccination time and the effect of Delta. But even in this regard, the decline may be limited. At the request of the FDA, Pfizer compared the difference in infection rates in populations with a median vaccination time of 9.8 months and 4.7 months in a Phase III clinical trial. People with shorter vaccinations do have a lower risk of infection, but the differences are limited in terms of effectiveness—if the effectiveness is 86% for those who are vaccinated for 4.7 months, then the corresponding effectiveness is 80% for those who have been vaccinated for 9.8 months [6].
Many studies have shown no significant decline in critical illness protection, such as a study by Pfizer in collaboration with Kaiser that found that the effectiveness of the vaccine against infections dropped to about 60 percent after four months of vaccination, but that critical care protection did not change at any age [6]. On September 22, Moderna published the final analysis of a Phase III clinical trial in the New England Journal of Medicine and found that in trials with an average tracking time of 5.3 months, the effectiveness of severe illness was 98% [7]. These studies all point to the fact that the mRNA vaccine's protection against severe diseases can be very long-lasting, apparently unable to support the urgent need for booster injections.
The strongest evidence to support the booster needle came from Israel. An Israeli study published in the New England Journal of Medicine before a meeting of FDA experts showed a 10-fold decrease in the risk of infection and a similar decrease in the risk of severe illness in people over the age of 60 after 12 days of receiving the booster needle [8]. But be aware that the study was tracked for less than two weeks after 12 days of receiving the booster needle. This raises the question of how long the validity can last. Meanwhile, Israeli health officials say that 60 percent of critically ill patients in the country are those who have received two doses of the vaccine, and for them, the effectiveness of protecting people from severe illness needs to be improved. However, in the United States, severe illness and hospitalization are still overwhelmingly unvaccinated [9], which raises questions about the prevalence and generalizability of the situation in Israel.
On the other hand, 70% and 87% of all cases of hospitalization or death due to breakthrough infections to date by CDC are older than 65 years of age [9]. It can be said that the elderly or people with underlying medical conditions are at greater risk of serious consequences if they develop a breakthrough infection. In addition, some studies collected by the CDC have shown that where the elderly gather, such as nursing homes, the effectiveness of the vaccine itself is low and there is a downward trend. From a risk-benefit perspective, there is stronger support for the implementation of booster needles in older adults.
In contrast, in the general population, the necessity of reinforcing needles not only lacks support, but it is also difficult to make a judgment that the benefits outweigh the risks. For the mRNA vaccine, the risk of myocarditis is known in young men, and although the incidence is low, the risk of a second dose is higher than that of the first dose. What the risks of a third dose are unknown. From the perspective of income, for young people, the protection against severe diseases after vaccination is very good, and there is no downward trend, and it is doubtful how much further benefits can be brought by the third injection on top of this.
Also based on these risk-benefit assessments, FDA experts will reject Pfizer's application for a comprehensive enhancement injection in people over the age of 16, instead limiting the population to people over the age of 65 and other high-risk groups. On September 22-23, the CDC's expert meeting to recommend vaccine use, on the basis of basically following the FDA approval scope, further restricted people over the age of 65 or living in long-term care centers, and patients aged 18-64 with underlying diseases that lead to an increased risk of severe illness, vetoed people at high risk of infection in the work within the SCOPE approved by the FDA. But in the CDC's formal recommendation, CDC Director Dr. Wallensky once again included high-risk populations at work.
This difference relates to different starting points in risk assessment, including people who are at high risk due to occupation or environment, and one of the more common reasons is that healthcare workers, even if mild, can not continue to work, which will affect the operation of the entire health system. However, in the view of outside experts at cdc, the risk-return criterion for booster needles should be centered on the vaccinator. For a young front-line worker, the most important benefit of enhancing for him personally - the prevention of severe illness, is very low, and the risk, such as rare myocarditis, is there, it can not be said that he is infected and can not go to work has an impact on society, it is recommended that he do a risk at the personal level may be greater than the benefits, not to mention that the benefits of the enhancement needle in the young population to prevent infection are now pure speculation.
There is a certain basis for recommendation and non-recommendation here, but it is more based on speculation, reflecting the many uncertainties caused by the limited data on the specific benefits of the enhancement needle.
Effects Outlook: Can Enhanced Needles Change the Outbreak?
Although many countries in Europe and the United States have been or will be giving enhancement injections to high-age and high-risk groups, the risk-return assessment of these groups may also be more likely to have more than risk, but the help to enhance the overall epidemic control may not be optimistic.
At the FDA's Enhanced Needle Expert Meeting, CDC epidemiologists acknowledged that the main transmission in the United States occurs in unvaccinated populations, so enhanced containment against the overall outbreak may be limited. This view was also shared by most of the experts attending the meeting.
Even in older adults whose direct benefits are likely to be greatest, the booster needle alone may not be optimal. At the CDC meeting on September 22 and 23 to discuss recommendations for the use of booster needles, CDC scientists provided simulations of the effects of booster needles in nursing homes. If the risk of importation is high (the infection rate is high in the area) and the vaccination rate of staff in the facility is low, even if the booster needle works well, there are still many cases of infection in nursing homes.
THE US CDC | on the simulation of the effect of reinforcing needles in nursing homes Image source[10]
For the booster needle to work well, it must be accompanied by controlling background infection rates and increasing staff vaccination rates. One of the biggest roles is to increase the vaccination rate of working people. This is also a microcosm of the entire epidemic in Europe and the United States. Increasing vaccination rates and getting the first shot of more unvaccinated people will be far more effective than enhancing the effect of the injection.
According to CDC estimates, to prevent a single case of COVID-19 hospitalization over a six-month period, only 50 initial vaccinations are required in people over the age of 65, but 481 doses are required for the booster needle, a gap of nearly 10 times [10]. If the age is lowered to 18-29 years old, this gap is further widened to 22 times, and at this age group, even the basic benefits outweigh the risks, and it is no longer certain for the enhancement needle. A CDC poll also showed that one-third of people who had not been vaccinated against COVID-19 expressed that the news of the booster would make them more reluctant to vaccinate [10]. An isolated policy of enhancing the needle may look limited in harm' effects, but there is uncertainty about what will happen to all anti-epidemic policies.
The number of initial vaccinations or booster vaccinations required to prevent a COVID-19 hospitalization within six months | Image source[10]
If you jump out of the small circle of developed countries in Europe and the United States, it is not difficult to find that the enhancement needle undoubtedly casts a greater shadow on the problem of unequal distribution of vaccines around the world. Of the COVID-19 vaccines already vaccinated, 81% are in high- and middle-income countries, with low-income countries receiving only 0.4%, while COVAX, which works to provide vaccines to low-income countries, recently cut the number of COVID-19 vaccines available this year by a quarter [11].
If outbreaks continue to spread in low-income countries with very low vaccination rates, it is difficult to guarantee that a mutant strain that is more dangerous than Delta will emerge in the future. European and American countries have emphasized that it will not affect the global vaccine supply when proposing the enhanced needle plan, but now the global vaccine demand is far greater than the supply, and it is difficult to imagine that the large-scale enhanced injection program in developed countries will not have a negative impact on global vaccination.
What do I need to do with the booster needle?
Although there are still many questions about the scientific principle and practical effectiveness of the enhanced needle, in the face of the global epidemic that is difficult to control in the short term, the enhanced needle is still a choice that needs serious consideration. Even in some populations, even if there is uncertainty about the enhancement needle, there is still a real need. In the face of such a reality, the research and decision-making of augmented needles need to develop in a more scientific and rational direction.
First, for enhancements to be performed now or in the near future, it is necessary to consider the actual demand and the potential benefit risks. The existing evidence of booster needles can be clear that the antibody can be greatly increased in the short term after vaccination, and what the corresponding actual effect is, if there is an effect, how long it lasts, is unknown. This makes there a lot of uncertainty about the benefits of enhancing the needle. In this case, if a person is at high or high risk due to age, underlying medical condition, or occupation, then it may be worth recommending an augmentation needle. However, if it is extended to the general population, then whether it is from the benefit risk of the individual vaccination or from the overall epidemic prevention consideration, the enhancement needle may not be worth the loss.
Secondly, the research of enhanced needles needs to be improved. Among the enhanced needles that have been announced, Pfizer/BioNTech data is the largest. But even so, clinical trial data for this vaccine booster needle is only more than 300 people, and it is impossible to evaluate the rare adverse effects of known mRNA vaccines such as myocarditis. In terms of effectiveness, immunization data are only antibody titers one month after vaccination. Real-world data on Israel is also only tracked for very short periods of time.
More detailed data on the immune response of the booster needle, especially changes in memory cells, cellular immunity, and the duration of the increase in antibodies, can help us determine whether to recommend the booster needle or change the inoculation procedure to three stitches.
Different vaccines may also be different. A preprinted paper on Sinopharm Vaccine showed that after the third injection half a year later, the antibody improved well, and it was maintained well for three months, and there was also an increase in memory cells and cellular immunity [12]. This may mean that the immune protection of the first two doses of inactivated vaccines can be continued to be perfected through subsequent vaccinations. However, the number of people in this trial was only 50 people, which is obviously insufficient to clearly enhance the safety of the needle and needs to be supplemented by follow-up studies. And from the perspective of improving immune protection, it is necessary to consider that the audience of the booster needle is a group that has obtained a certain amount of immune protection through initial vaccination, the immunogenicity of inactivated vaccines is low, and with some more effective vaccines such as recombinant protein vaccines on the market, it should be considered to determine a more efficient booster shot through mixed studies.
Not only in Europe and the United States began to implement the enhanced needle, but also the domestic high-risk personnel also began to recommend additional enhancement injections after six months of inactivated vaccines. In the face of a virus that we have known for less than two years and a rapidly changing epidemic, many times our decisions have to be based on relatively incomplete information, and the same is true for the augmentation needle. This prompts us to refine the relevant research as soon as possible, supplement the completeness of the relevant data, and also remind ourselves that we need to be cautious in making decisions on the lack of information.
Resources
1.https://www.biorxiv.org/content/10.1101/2021.07.29.454333v1.full
2.https://www.biorxiv.org/content/10.1101/2021.08.23.457229v1.full
3.https://www.science.org/doi/10.1126/science.abj4176
4.https://www.medrxiv.org/content/10.1101/2021.08.09.21261290v4
5.https://www.timesofisrael.com/virus-czar-calls-to-begin-readying-for-eventual-4th-vaccine-dose/
6.https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-september-17-2021-meeting-announcement#event-materials
7.https://www.nejm.org/doi/full/10.1056/NEJMoa2113017
8.https://www.nejm.org/doi/full/10.1056/NEJMoa2114255?query=featured_coronavirus
9.https://www.cdc.gov/vaccines/covid-19/health-departments/breakthrough-cases.html
10.https://www.cdc.gov/vaccines/acip/meetings/slides-2021-09-22-23.html
11.https://www.nytimes.com/2021/09/08/health/covax-global-covid-vaccine-boosters.html
12.https://www.medrxiv.org/content/10.1101/2021.09.12.21263373v1.full-text