Bivalent and Monovalent SARS-CoV-2 Variant Vaccine Boosters Improve coverage of the known Antigenic Landscape: Results of the COVID-19 Variant Immunologic Landscape (COVAIL) Trial (preprint)

Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT 05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Reactogenicity, Safety, and Serological and Cellular Immunogenicity of a Booster Dose of SARS-CoV-2 mRNA Prototype, Variant, and Bivalent Vaccines (preprint)

Waning immunity after two SARS-CoV-2 mRNA vaccinations and the emergence of variants precipitated the need for booster doses. We evaluated safety and serological and cellular immunogenicity through 6 months after a third mRNA vaccination in adults who received the mRNA-1273 primary series in the Phase 1 trial approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA-1273.351 that encodes Beta variant spike protein, and bivalent vaccine of 25 mcg each of mRNA-1273 and mRNA-1273.351. A third dose of mRNA vaccine appeared safe with acceptable reactogenicity. Vaccination induced rapid increases in binding and neutralizing antibody titers to D614G, Beta, Delta and Omicron variants that persisted through 6 months post-boost, particularly after administration of Beta-containing vaccines. Spike-specific CD4 + and CD8 + T cells increased to levels similar to those following the second dose. Boost vaccination induced broad and durable humoral and T cell responses. ClinicalTrials.gov numbers NCT04283461 (mRNA-1273 Phase 1) and NCT04785144 (mRNA-1273.351 Phase 1)

Safety and Immunogenicity of a Third Dose of SARS-CoV-2 mRNA Vaccine — An Interim Analysis (preprint)

Waning immunity after two SARS-CoV-2 mRNA vaccinations and the emergence of variants precipitated the need for a third dose of vaccine. We evaluated early safety and immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary series in the Phase 1 trial approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA-1273.351 that encodes Beta variant spike protein, and bivalent vaccine of 25 mcg each of mRNA-1273 and mRNA-1273.351. A third dose of mRNA vaccine appeared safe with acceptable reactogenicity. Vaccination induced rapid increases in binding and neutralizing antibody titers to D614G, Beta, and Delta variants that were similar or greater than peak responses after the second dose. Spike-specific CD4+ and CD8+ T cells increased to similar levels as after the second dose. A third mRNA vaccination was well tolerated and generated robust humoral and T cell responses. ClinicalTrials.gov numbers NCT04283461 (mRNA-1273 Phase 1) and NCT04785144 (mRNA-1273.351 Phase 1)

Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants (preprint)

SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, and the durability of such responses has not been previously reported. Here, we present a comprehensive assessment of the impact of variants B.1.1.7, B.1.351, P.1, B.1.429, and B.1.526 on binding, neutralizing, and ACE2-blocking antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive neutralizing responses were rare after a single dose of mRNA-1273. At the peak of response to the second dose, all subjects had robust responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of mRNA-1273. Across all assays, B.1.351 had the greatest impact on antibody recognition, and B.1.1.7 the least. These data complement ongoing studies of clinical protection to inform the potential need for additional boost vaccinations.

Endpoints for randomized controlled clinical trials for COVID-19 treatments (preprint)

Introduction: Endpoint choice for randomized controlled trials of treatments for COVID-19 is complex. A new disease brings many uncertainties, but trials must start rapidly. COVID-19 is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks and can end in death. While improvement in mortality would provide unquestionable evidence about clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly in relating to the uncertainty about the time-course of COVID-19. Outcomes measured at fixed time-points may risk missing the time of clinical benefit. An endpoint such as time-to-improvement (or recovery), avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" vs "not recovered." Methods: We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials. Results: Power for fixed-time point methods depends heavily on the time selected for evaluation. Time-to-improvement (or recovery) analyses do not specify a time-point. Time-to-event approaches have reasonable statistical power, even when compared to a fixed time-point method evaluated at the optimal time. Discussion: Time-to-event analyses methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.