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Are two doses enough? Third dose or new vaccines: variants complicate the horizon of immunization

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Pharmaceutical companies are already investigating new vaccine variants to respond to mutations and booster doses may be necessary

The end point of the pandemic story should be written when everyone has received the second dose of the vaccine. The hope that guiding the actions of the health authorities in recent months, since it became clear that we were going to have more or less effective protection against covid and plans to immunize most of the population began to be designed as quickly as possible. However, the appearance of variants has clouded that horizon.

Until a few weeks ago, the most important question was how long the immunity that the vaccines would provide us would last, and it did not seem very worrying because it would be solved by receiving the same injections again. However, the mutations found in the UK, South Africa, and Brazil raise more questions. Regardless of whether they may be more transmissible or more lethal, worsening the current situation, the most important thing is to know if the vaccines will be able to neutralize them with the same forcefulness as the virus that we knew.

In fact, the new vaccines that will be developed in the near future have lower efficacy than the first ones. While Pfizer and Moderna reached 95%, Novavax has remained at 89.3% and Janssen at 66%. It is largely explained why their clinical trials have already been conducted with the new variants in circulation. Thus, when dissecting the data, the Novavax vaccine has an efficacy of less than 50% against the South African variant and the Janssen vaccine remains at 57%, which influences the overall data. For the two vaccines, there is no concrete data on the South African variant; neither for AstraZeneca (with 62% efficiency) nor for the Russian Sputnik V (92%).

The variant found in South Africa and Brazil, playing an important role in the reinfections of many patients in Brazil, and Africa, causing a catastrophic situation. Some studies with serum from convalescent patients show that this change could allow the virus to evade the antibodies of people who have already overcome the disease. Now, a report from British health authorities indicates that the English variant could also have acquired the E484K mutation from the South African and Brazilian variants. Therefore, the concern for the new variants is increasing day by day.

Given these new circumstances, it is becoming increasingly difficult to think that the double dose of the vaccines already available will be sufficient. In fact, the German Minister of Health, Jens Spahn, assured days ago that his country has reserved the vaccines for 2022 in anticipation of the need for booster doses. Along the same lines, Moderna has already announced that it will test the effect of the third dose of its vaccine. The idea is to study whether an additional injection would increase protection against emerging variants, even without modifying the current vaccine.

However, the safest bet would be to make the vaccine to neutralize the new variants. For this reason, Moderna is also studying a modification of its treatment that would be directed specifically against the South African variant. Specifically, it is conducting preclinical studies and in the US, it already has a trial with patients, at the moment, in phase 1.

This does not mean that they will start from scratch. Messenger RNA vaccines – both the one from Moderna as well as from Pfizer and BioNTech – include this genetic material to give instructions to our cells so that they are the ones that manufacture the antigen that will induce the immune response, in this case, the S protein of the virus. Modifying the vaccine would make it possible to manufacture this spike protein with the changes it has in the South African variant or in any other, and everything could be done quite quickly. By design and manufacturability, RNA-based vaccines would have a certain advantage in developing new versions very quickly. In fact, the manufacturers themselves talk about that the process could be completed in about six weeks.

In any case, it is still too early to know in what situation the current vaccines will leave us. According to experts, “if we vaccinate most of the population with those that are already available, we are really going to greatly reduce the effects of the coronavirus“.

However, when that time comes, decisions will have to be made based on the epidemiological situation, which in no case would be as dramatic as the current one, when we are still largely unprotected. For example, giving a booster dose only to certain population groups may be sufficient.

Like Moderna, Pfizer and BioNTech try to anticipate and have recently conducted studies on the new variants using serum from people who have already received their vaccine. In principle, everything indicates that it would continue to protect against all the SARS-CoV-2 variants tested, although the neutralization of the virus is “slightly less”, as recognized. However, these companies consider it “unlikely that the small differences in viral neutralization observed in these studies will lead to a significant reduction in the efficacy of the vaccine.”

The truth is that the ‘in vitro’ results do not have to correspond to reality, so these companies continue to investigate and claim to be prepared to develop a new version of their vaccine if a variant of the virus proves to be capable of escaping immunity generated. “Every time a new variant comes up we should be able to test whether or not [our vaccine] is effective,” Pfizer CEO Albert Bourla told Bloomberg a few days ago. If something goes wrong, “we will very, very quickly be able to produce a booster dose that will be a small variation to the current vaccine.”

Towards a regular vaccination?

The scenario that Bourla seems to draw in these statements is very similar to the flu: constant surveillance of new strains to adapt vaccines quickly. In fact, every year a new vaccination campaign has to be organized that is especially aimed at certain groups, such as the elderly and health workers. However, the coronavirus is different, especially because its ability to generate mutations is much lower. 

In the case of influenza there is an active surveillance system around the world to detect mutations and to be able to detect specific vaccines that change annually. Thinking that something like this could happen with new strains of SARS-CoV-2, right now, doesn’t make much sense. However, if necessary, one of the lines of research that is being worked on is the possible joint administration of the flu and covid vaccines.

With this panorama, many questions remain to be answered. One of them is whether a new version of current vaccines or even a new vaccine would have to be administered with the two-dose schedule that we already know even to people who have already been vaccinated before. “It is possible that the first exposure to the antigen is already useful and that with only one dose directed at a new variant a more specific immunity is already achieved. This is precisely one of the aspects that have to be rehearsed in order to have data if the time comes,” according to some experts.

Current variants share many mutations, but if they became very different, would a single vaccine be enough or would we have to receive different doses to immunize ourselves against different strains or variants of the coronavirus? Experts believe that given this possibility, it would be difficult to have a single vaccine against all variants, at least as the main ones have been designed so far, although there are possibilities that should be investigated.

Everything could be different if vaccines not only help prevent the disease but also stop the transmission of the virus. This question is one of the great unknowns. Research from the University of Oxford indicates that AstraZeneca treatment could reduce the circulation of the virus among those vaccinated by 67%. Although it is only a ‘preprint’, an article not yet reviewed by other experts, the UK Secretary of State for Health, Matt Hancock, has already celebrated the news on Twitter.

However, not everyone is clear that the results can be interpreted in this way since the study was not really designed to measure transmission and the figure comes from a statistical combination.

In any case, if the vaccines finally had that effect and cut the chain of infections, would it be possible to eradicate the coronavirus and avoid those periodic punctures? In this scenario, it would not be unreasonable to think that the double dose provided by most current vaccines would be more than enough or, at most, some booster dose for the new variants.

In this sense, there are two key questions. On the one hand, if the virus circulates less, it will have less chance of mutating. On the other, the virus will be more pressured, because if there is no transmission and people are protected, it will only be able to circulate if there is a mutation that escapes immunity. 

In short, if vaccines achieve their goal, “only viruses that mutate will survive.”

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