Leaving more than 12 million infections, more than 550,000 deaths and an economic cost of billions of dollars to date,one The SARS-CoV-2 pandemic has devastated the most vulnerable in our society: adults 65 years of age or older, people with underlying conditions, and economically disadvantaged people.two A vaccine is urgently needed to prevent Covid-19 and, therefore, to stop complications and deaths resulting from transmission of the disease.
Jackson et al. now report on the diary Preliminary results of a phase 1 trial to assess the safety and immunogenicity of a SARS-CoV-2 mRNA vaccine.3 Phase 1 involves 45 healthy adults, ages 18 to 55, who were assigned to receive the candidate vaccine at one of three dose levels (25 µg, 100 µg, or 250 µg) administered in two 28-day vaccines. Of diference. These preliminary findings represent the first of three reports of data from a phase 1 study of this candidate vaccine; A second report is also planned that includes similar data from adults over 55 and a final report summarizing the safety and durability of immunity for both study cohorts.
Traditional way of vaccine development.
The speed with which this vaccine has been developed is remarkable: from the publication of the first SARS-CoV-2 sequences to phase 1 in 6 months, compared to a typical timeline of 3 to 9 years (Figure 1) The rapid rate of development of Covid-19 vaccines is enabled by several factors: prior knowledge of the role of the spike protein in the pathogenesis of the coronavirus and evidence that the neutralizing antibody against the spike protein is important for immunity.4.5; The evolution of nucleic acid vaccine technology platforms that enable vaccine creation and the rapid manufacture of thousands of doses once a genetic sequence is known6 6; and development activities that can be carried out in parallel, rather than sequentially, without increasing 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 take into account the complexity of vaccine development and the work that remains to be done before Covid-19 vaccines become widely available.
Many phase 3 studies fail due to incorrect identification of the dose that best balances safety and efficacy.7 7 The dosage regimen for this mRNA vaccine is still under study. The 250 µg dose did not appear to be associated with markedly higher antibody titers than the 100 µg dose, but was associated with a higher proportion of serious systemic adverse events. As the researchers indicate, it is prudent to evaluate doses of 100 μg and less to define the regimen that provides the most appropriate risk-benefit profile for this vaccine. Another special dosing consideration in this case is age: immune functions that decline with age and are likely responsible for the increased risk of severe Covid-19 in older adults may also lead to poor vaccine responses. Will a high dose of the Covid-19 vaccine be needed for effective protection of older adults, as seen with influenza vaccines?8
It will be necessary to confirm the clinical importance of neutralizing and SARS-CoV-2 binding antibody titers and their ability to predict efficacy. These measures are currently being used to guide dose selection before being verified; they are the best tools available and are backed by findings 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, it will also be necessary to document the validity of the assays to measure antibodies. These assays are remarkably variable because they use live virus or protein expression in cell cultures with a reading that is based on an in vitro biological reaction (i.e. binding of antibodies in serum or removal of viral antigen). Optimizing the performance characteristics of these assays will be invaluable in streamlining development and supporting the bridge across diverse populations and manufacturing processes.
The authors indicate that a planned phase 3 trial of this SARS-CoV-2 mRNA vaccine is imminent; The trial will require thousands of subjects to confirm the safety of the vaccine and show statistically robust efficacy in preventing 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 match between the location of the vaccinated participants and the pandemic hot spots. Uncertainty regarding the expected efficacy profile also generates complexity; The profiles observed for other viral vaccines suggest that the efficacy against severe Covid-19 may be greater than the efficacy against mild disease. Careful selection of primary end points and event-based study designs with the possibility of re-estimating sample size should be considered.
Accelerating the development of Covid-19 vaccine candidates beyond phase 1 depends on continued parallel monitoring of activities and abundant resources. The world has witnessed the compression of 6 years of work in 6 months. Can the multiverse vaccine do it again, leading to a reality of a safe and effective Covid-19 vaccine for the most vulnerable in the next 6?
