Source : 'The Pink Sheet'
“Both trials appeared to be well designed,” based on publicly available information, said Ira Longini, co-director of the Center for Statistics and Quantitative Infectious Diseases Emerging Pathogens Institute at the University of Florida. But he added they suffer from the fact that they’re done independently.
“They’re different enough, so it’s going to be hard to compare the outcomes when we have them.” Longini is doing work with the World Health Organization’s Solidarity Trial, a master protocol study to test COVID-19 treatments.
Both Moderna and Pfizer announced vaccine candidates that were headed into late-stage studies this week. Moderna’s Phase III trial is expected to enroll 30,000 adult volunteers who do not have COVID-19. The primary endpoint is whether the vaccine can prevent symptomatic COVID-19 after two doses. ("Modernas COVID-19 Vaccine To Get Real-Time Data Assessment By US FDA" "Pink Sheet" )
Pfizer also expects to enroll about 30,000 patients in a study that will asses confirmed COVID-19 in participants without evidence of infection before vaccination and confirmed COVID-19 in participants with and without evidence of infection before vaccination.
Moderna is hoping to secure a higher price for its vaccine than Pfizer has, and it’s unclear whether the inability to directly compare the two studies will work for or against it as the data is revealed. (See sidebar.)
A key distinction between the trials is Moderna’s decision to exclude patients with a known history of SARs-CoV-2 infection.
Longini said he thinks “it’s probably more important” to not exclude these patients. Excluding people who have had the virus might get a trial to an answer sooner, because the population might have a higher infection rate, he said. But given that it’s still unknown what, if any, immunity people with prior infection have and that in practice people won’t be screened for prior infection prior to vaccination following approval, it’s important to understand the safety and efficacy of a vaccine in this population, he explained.
Paul Offit, Director of the Vaccine Education Center at the Children’s Hospital of Philadelphia agreed that Pfizer’s approach is the “smarter way to go.” It is the more “practical way to do it because it’s the way its going to play out in the real world,” he said.
The US Food and Drug Administration guidance on COVID-19 vaccines says vaccine safety and COVID-19 outcomes in individuals with prior infection is important to examine because pre-vaccination screening for prior infection is unlikely to occur when a vaccine is delivered post-market. The agency guidance says trials “need not screen for or exclude participants with history or laboratory evidence of prior SARS-CoV-2 infection.”
Moderna is the first of the four confirmed companies that are part of the US government’s Operation Warp Speed project to quickly advance coronavirus vaccines. Its unclear if other trials will follow the same exact protocol but the government is trying to harmonize the trials.
Offit noted one benefit of Warp Speed is that the government can work to have a central lab for trial samples to make it easier to compare the vaccines it is working on. But Pfizer, unlikely Moderna and other leading candidates, has elected not to participate in Warp Speed. AstraZeneca PLC, Janssen Pharmaceuticals Inc. and Novavax, Inc. round out the other Warp Speed participants.
At the a meeting of the Center for Disease Control and Prevention’s Advisory Committee on Immunization Practices on 29 July, Julie Ledgerwood, deputy director and chief medical office of the vaccine research center at the National Institute of Allergy and Infectious Diseases, described the Warp Speed trial approach as “semi-independent harmonized trials” which will include collaborating labs on issues like defining COVID infections and T-cell responses.
Other shared principles of the OWS trials include the primary endpoint of prevention of symptomatic COVID-19 disease, virologic confirmation, and a common data safety monitoring board managed by the NIAID.
For Pfizer and BioNTech SE, their pivotal trial will actually use their ‘backup’ COVID-19 vaccine candidate after finding that it could provide a greater T-cell immune response in older in patients and greater tolerability.
The companies will now take their BNT162b2 vaccine candidate into the Phase II/III study, rather than BNT162b1, its closely related variant which performed well in recently presented Phase I results. The decision to switch followed a careful analysis of data from Phase I trials. While BNT162b1 had the edge on antibody responses, BNT162b2 had a better tolerability profile and signs of a stronger response in T-cells. The collaboration has developed four separate mRNA-based candidates until now, two which target the virus’ full-length spike protein, and two which target just the key receptor binding domain (RBD). The new lead candidate targets the full spike protein, which could help it generate a greater T-cell response. The companies said BNT162b2 showed signs that it could be more effective in older age groups, which will be the real test of any COVID-19 vaccine, as these are more vulnerable to the virus than younger people, but also generally produce a less robust immune response to vaccines. In older adults (65-85 years of age), two 30 µg doses, spaced three weeks apart, the vaccine candidate elicited a neutralizing antibody geometric mean titer (GMT) higher than that in a panel of 38 sera from subjects who had contracted SARS-CoV-2. BNT162b2 vaccinated human participants also displayed a favorable breadth of epitopes recognized in T-cell responses specific to the SARS-CoV-2 antigen, as compared to the BNT162b1 candidate. The partners said BNT162b2 demonstrated concurrent induction of high magnitude CD4+ and CD8+ T-cell responses. It also elicited T-cell responses against the receptor binding domain (RBD) and against the remainder of the spike glycoprotein that is not contained in the BNT162b1 vaccine candidate. “Immune recognition of more spike T cell epitopes may have the potential to generate more consistent responses across diverse populations and in older adults,” the firms said.
By Sarah Karlin-Smith