The Seven Big Questions That Surround The Covid 19 Vaccines
Health

The seven big questions that surround the Covid-19 vaccines

Researchers don’t yet know if it will be possible to create broad-spectrum vaccines or if combining two different doses can boost immunity.

AstraZeneca vaccine.

From the point of view of a global pandemic, the biggest challenge facing a vaccine is accessibility. For a vaccine against a pandemic to be effective, we have to get it everywhere. Even if it’s just selfishly, We cannot afford places where the virus is at home, evolve and attack us again.

This implies overcoming four limitations: producing sufficient quantities, that can be stored easily, that the supply is not interrupted and that the cost is affordable to any country in the world. From the point of view of the technical design of vaccines, we still have certain questions.

How much does a virus have to mutate for the vaccine to stop being effective?

We have conflicting information on the neutralizing capacity of the South African, Brazilian and Indian variants of the antibodies generated in patients who have been vaccinated or recovered from the infection. More studies and larger cohorts are needed to draw more real and less ambiguous conclusions.

How will the vaccine update be? How much effort does it cost to redesign a vaccine?

For RNA vaccines and viral vectors, it is relatively simple, because they only have to synthesize a new fragment of DNA (adenovirus), or modified RNA (Pfizer and Moderna) as appropriate, and then insert it into the new vaccine.

In addition, tests in animals and humans will be necessary to show that the new version can generate immune responses and that it remains safe.

Another more sophisticated alternative would be to develop vaccines with a combination of spike RNAs that cover the different sequences that arise and are of interest for their immune escape properties.

Is it possible to generate broad-spectrum vaccines that cover all coronaviruses?

Coronaviruses have brutally threatened humanity in the last 30 years. Let us remember the first cousins โ€‹โ€‹of this SARS-CoV-2, SARS and MERS, which fortunately remained in epidemics but had much higher fatalities than covid-19.

Paleopathology and epidemiology studies suggest that the so-called Russian flu at the end of the 19th century perhaps it was the first coronavirus pandemic in history.

Today there is a great consensus that the threats of the future will no longer be just new variants and zoonoses of the influenza virus, but that we will have to think about new coronaviruses as well.

Can we reduce the interval between doses or get a single dose vaccine?

This aspect is important, since we know that the antibodies that are generated against the virus force it to mutate to escape the pressure of the immune system. After the first dose we have the primary response antibodies, which are less effective and less abundant than those generated after the second dose, those of the secondary response.

The longer the duration of the primary response (time between vaccinations), the more likely the virus is to generate escape variants.

Therefore, adenovirus vaccines were designed to generate primary and secondary immunity with a single dose. But they had a subgroup where they gave two doses, and they found that they had much better immune responses. This prompted them to consult with regulators and they agreed to move to a two-dose strategy.

In fact, the Johnson & Johnson (Janssen) adenoviral vector vaccine is a single dose but with less overall efficacy than the others and the incorporation of a second dose is being studied.

Can we combine different vaccines?

We have to reduce the immunogenicity of vaccines. And in this sense, the combination of different vaccines is another possible approach that could improve the overall flexibility and performance of the vaccine.

The biggest problem facing the combination is that they have been designed and produced by different companies and it is sometimes impossible to combine interests and procedures to be able to carry out tests.

In current formulations, the 3 adenovirus vaccines involve different combinations of adenovirus variants: the Sputnik V vaccine uses Ad26 for the first dose and then Ad5 for the second dose. The AstraZeneca vaccine uses ChAdeno and then the same ChAdeno again. The Johnson & Johnson vaccine uses Ad26 (it would later use Ad26 in the 2-dose version).

The higher efficacy reported for the Russian Sputnik V vaccine, which uses two different human adenoviruses, suggests the possibility that immunity against the vector compromises the efficacy of a second dose of identical adenovirus. To overcome any problems related to anti-vector immunity, using an mRNA or protein vaccine to boost the first dose of Johnson & Johnson’s or AstraZeneca’s adenovirus vectors might be more effective than giving a second dose of the same adenovirus.

In fact, in several countries, due to thromboembolic problems, a first dose of adenovirus and a second of mRNA will be proceeded in this way, even in the absence of clinical trials to support it.

In the case of having to reimmunize every year or with certain frequency, how will people already vaccinated respond?

On the one hand we have the problem of the vector already discussed: we will not be able to use it again so as not to lose efficiency. But there is another problem that is no less important and more difficult to solve, and that is how much the virus spike changes from one variant to another.

The protein has nearly 1,300 amino acids, only one or very few of which vary from one variant to another. With the first immunizations, antibodies are generated against the complete protein. If we vaccinate with an almost identical protein, the production of already existing memory antibodies will be reinforced and this can make it statistically difficult for the new amino acids of the variants to be immunogenic and therefore it will not be possible to generate powerful immunity against the new variants.

Is it possible to restrict the use of less effective vaccines to young people, more asymptomatic and with less load and easier to neutralize?

It does not seem like a far-fetched idea, since they suffer from the disease with less virulence.

The example of measles

Finally, we have to educate the population to accept to put on what has been assigned to them. We are experiencing an excess of information in real time, which on certain occasions can be bad information.

I am referring to the case of AstraZeneca, where the benefits clearly outweigh the risks. There is fear and distrust in the population and this feeling leads to the rejection of some vaccines, which is not good for the control of the disease.

In 1963, vaccination against measles began, possibly the most contagious disease in the world (R0โ‰ƒ15). As measles does not have reservoirs outside of humans, a good global campaign seemed to make its worldwide eradication a feasible goal. The campaign reduced the incidence of measles but did not eradicate it.

Inequities in its administration led to measles becoming disproportionately a disease of black and Hispanic children.

This problem was resolved, but the anti-vaccine movement caused many babies to go back to not being vaccinated and therefore outbreaks are being observed in the United States.

This story of the measles vaccine reminds us that we have an obligation to provide equitable access and clear information to everyone. That doubt and mistrust can undermine the effectiveness of safe and effective vaccines and valuable public health initiatives.

Planning for the implementation of SARS-CoV-2 vaccination requires not only working out details of distribution, priority, and cold chains, but also strategies to reach people who are suspicious, hesitant, doubtful, or outright opposed.

*This article was originally published on The Conversation.

**Rafael Sirera is Professor of Cell Biology at the Polytechnic University of Valencia.