Home » Covid, pay attention to third doses: better not to continue with RNA vaccines

Covid, pay attention to third doses: better not to continue with RNA vaccines

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Although there are several reports with credible data on a substantial duration of protective immunity against Covid-19 in both healed over one year and fully immunized (two doses) subjects of current gene vaccines, there remains a widespread belief that ultimately SARS -CoV-2, the perfidious crowned one, will not be eradicated. That is, it will become endemic, perhaps with mild-moderate disease, flu-like, against which at least those at risk will have to revaccinate annually – or at different intervals -.

The question then is: with which vaccine? Given the high efficacy and acceptable safety profile demonstrated by the two RNA vaccines in the primary vaccination, the answer would seem obvious: we do another dose of one or the other of these two vaccines, suitably modified to take into account variants. Unfortunately it is not that simple and the experience with this unpredictable virus does not follow the laws of Monsieur Lapalisse.

The vaccines we are using are still authorized in an emergency, that is, they are awaiting final approval from the regulatory bodies. They are waiting to learn more, not only on the long-term vaccine efficacy but also, and above all, on the safety profile of the two doses. Moreover, it may be useless to proceed with this approval given that Pfizer-BionTech and Moderna are already changing the vaccine antigen to take into account the variants, as mentioned above. In any case, it will be RNA molecules, perhaps with the addition of sequences, such as those of the coronavirus nucleoprotein antigen, which can broaden the range of antibody and protective cellular responses.

There is debate on the subject and news are on the horizon. But the important question now is: we have sufficient evidence that repeated RNA injections, even if months or years later, meet the safety requirement, which certainly has a higher stick for routine booster vaccination, in people already vaccinated, than what we accepted for emergency vaccination? The answer is that there is no proof because there is a lack of experimentation on the subject. Indeed, there are biological, clinical and experimental indications in laboratory animals that lead us to believe that multiple administrations of RNA, at least of how this molecule is currently prepared, may not be acceptable.

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We note, first of all, that unlike common non-gene vaccines, RNA vaccines are generally more reactogenic at the second dose than the first, particularly with regard to systemic adverse events, such as fever, headache and widespread malaise. In addition to the results of clinical trials, this is also evident from the first but already abundant pharmacovigilance data despite the limitations of the passive notification system. The latest AIFA report (n-5) regarding the reporting of adverse events after administration of the most widely used RNA vaccine in Italy (Comirnarty, by Pfizer -BionTech) reports that adverse events such as hyperpyrexia, headache, joint and muscle pain are associated between them, “realizing a picture of flu-like syndrome, more often reported as a serious reaction, another clinically relevant condition” (textual AIFA), after the second dose of Comirnaty.

But there is much more to preclinical literature. The systemic administration of RNA molecules is still associated, right from the first therapeutic applications, with toxicity if repeated frequently even when, as in the case of vaccines, the sequence is modified both to increase stability and immunogenicity and to reduce it. the immunotoxic effects. However, these are molecules that strongly activate the immune system, recognized by a multiplicity of cellular receptors. While this is an advantage for the first few doses, if they are repeated at short intervals they can even cause a reduction in immunizing capacity, as claimed by a well-known expert in the field, Margaret Liu, formerly an academic at Harward. With these assumptions, an extensive clinical trial prior to use remains a must. If the idea is, as some argue, to give us a nice new RNA administration next autumn, perhaps together with the flu vaccine, (Moderna is already preparing it), it is hoped that the data of this experiment will be made available as soon as possible.

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There is, however, another possibility, to be carefully evaluated, even if it requires adequate experimentation. Vaccines whose technology has long been known for its safety even after multiple administrations, particularly in pediatric subjects, are present or in the pipeline, see the hepatitis vaccine and the various acellular pertussis vaccines. It is about subunit vaccines, with recombinant proteins. One of these, closest to approval, is the vaccine Novavax, where the coronavirus trimeric Spike protein, not its RNA code, represents the immunizing antigen. It is a recombinant protein obtained in insect (moth) cell lines, formulated as an adjuvant nanoparticles. In the clinical trial just completed, this vaccine was found to be just as immunogenic and in fact as protective as the two RNA vaccines, but with a decidedly lower reactogenicity and, as used for these vaccines, the low reactogenicity was the same or lower after the second dose. This clearly results from the first, albeit partial, data published in the New England Journal of Medicine. Of the protein subunit vaccines we have long experience of repeated boosters, even after a short distance (months) without significant side effects. Other protein subunit vaccines are in the pipeline and we expect conclusive data shortly.

It will be difficult for these vaccines to find adequate space as primary vaccination in countries, such as ours, where within a few months almost the entire population candidates for vaccination will in fact be immunized. Their space is especially designed for those countries with low vaccination coverage. For us, however, their space is probably that of heterologous references, as publicly claimed, in a recent interview with New York Times, gives Luciano Berio, a former chief scientist of the Food and Drug Administration. Protein subunit or inactivated vaccines such as two of China’s Sinovac vaccines are excellent candidates for heterologous RNA vaccine boosters not only for their safety but also for the simplicity of logistics, distribution and cold chain. It is hoped that these vaccine booster candidates will soon undergo adequate clinical trials.

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In conclusion, it seems wise not to accept as the only and obvious necessity that those who have made an RNA vaccine continue to do so over the years. Waiting to know if we really need annual boosters of the anti-Covid-19 vaccine, let’s get ready to accept, after experimentation, even boosters with different vaccines. Here, perhaps even more so than the Astra Zeneca-Pfizer relay, the diversity of vaccine formulations may be beneficial in the fight against this disease. Will a genetic code followed by its protein be the most appropriate and perhaps necessary future vaccination strategy?

* Member of the American Academy of Microbiology; former director of the Department of Infectious, Parasitic and Immune-mediated Diseases of the ISS, Rome

** Full Professor of Infectious Diseases at the Catholic University, Rome

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