The Covid-19 Vaccine Development Multiverse | NEJM

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Leaving in its wake more than 12 million infections, more than 550,000 deaths and an economic balance of several billion dollars to date,1 the SARS-CoV-2 pandemic devastated the most vulnerable in our society – adults aged 65 and over, people with underlying illnesses and the economically disadvantaged.2 A vaccine is urgently needed to prevent Covid-19 and thus stem the complications and deaths resulting from the transmission of the disease.

Jackson et al. report now in the Journal preliminary results from a phase 1 trial to assess the safety and immunogenicity of a SARS-CoV-2 mRNA vaccine.3 Phase 1 concerns 45 healthy adults, aged 18 to 55, who have been assigned to receive the candidate vaccine at one of three doses (25 μg, 100 μg or 250 μg) administered in two vaccinations at 28 days interval. These preliminary results represent the first of three data reports from a phase 1 study of this candidate vaccine; a second report including similar data from adults over 55 and a final report summarizing the safety and durability of immunity for the two study cohorts is also planned.

Route of development of traditional vaccines.

The speed with which this vaccine was developed is remarkable – from the publication of the first sequences of SARS-CoV-2 to phase 1 in 6 months, compared to a typical delay of 3 to 9 years (Figure 1). The rapid rate of development of vaccines against Covid-19 is made possible by several factors: prior knowledge of the role of advanced protein in the pathogenesis of coronaviruses and proof that the neutralization of antibodies against advanced protein is important for immunity4,5; the evolution of technological platforms for nucleic acid-based vaccines that allow the creation of vaccines and the rapid production of thousands of doses once a genetic sequence is known6; and development activities that can be carried out in parallel, rather than sequentially, without increasing the risks for study participants.

The safety and immunogenicity data in this preliminary report are promising and support the continued development of this vaccine. However, we must keep in mind the complexity of vaccine development and the work that remains to be done before Covid-19 vaccines are widely available.

Many phase 3 studies fail due to incorrect identification of the dose that best balances safety and efficacy.7 The dosing schedule for this mRNA vaccine is still under study. The 250 μg dose does not appear to be associated with significantly higher antibody titers than the 100 μg dose, but is associated with a higher proportion of severe systemic adverse events. As the investigators indicate, it is prudent to evaluate doses of 100 μg and less to define the treatment regimen offering the most appropriate benefit / risk profile for this vaccine. Another particular dosage consideration in this case is age: immune functions which decrease with age and which are likely to be responsible for the greatest risk of severe Covid-19 in the elderly can also lead to poor vaccine responses. Will a high-dose Covid-19 vaccine be necessary for effective protection of the elderly, as has been observed with influenza vaccines?8

The clinical significance of the SARS-CoV-2 binding and neutralizing antibody titers and their ability to predict efficacy will need to be confirmed. These measurements are currently used to guide the selection of doses before being verified; these are the best tools available and are supported by discoveries in non-human primates.9 Confirmation of the correlation between antibody titers and protection against Covid-19 will only be possible in a large clinical efficacy study. In the meantime, the validity of antibody measurement tests should also be documented. These tests are notoriously variable because they use the viral or living protein expression in cell culture with a reading which is based on a biological reaction in vitro (that is to say that the serum antibodies bind or kill the viral antigen) . Optimizing the performance characteristics of these tests will be invaluable in streamlining development and supporting bridging between populations and various manufacturing processes.

The authors indicate that a planned phase 3 trial of this mRNA vaccine against SARS-CoV-2 is imminent; the trial will require thousands of subjects to confirm the safety of the vaccine and demonstrate statistically robust efficacy in the prevention of Covid-19. The operational complexity inherent in a large study is compounded by the ripples of the pandemic; efficacy can only be determined if there is a correspondence between the location of vaccinated participants and pandemic hotspots. Uncertainty about the expected efficacy profile is also a source of complexity; patterns seen for other viral vaccines suggest that efficacy against severe Covid-19 may be greater than efficacy against mild disease. A careful selection of primary evaluation criteria and event-driven study plans should be considered, with the possibility of re-estimating the sample size.

The acceleration of the development of Covid-19 vaccine candidates beyond phase 1 depends on continuous parallel monitoring of activities and full resources. The world has now witnessed the compression of 6 years of work in 6 months. Can the vaccine multiverse start again, leading to the reality of a safe and effective Covid-19 vaccine for the most vulnerable of the next 6?

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