SARS-CoV-2 Variant Vaccine Boosters Trial: Preliminary Analyses

Abstract

Background: Protection from SARS-CoV-2 vaccines wanes over time and is compounded by emerging variants including Omicron subvariants. This study evaluated safety and immunogenicity of SARS-CoV-2 variant vaccines. Methods: This phase 2 open-label, randomized trial enrolled healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single boost. Eligible participants were randomized to one of six Moderna COVID19 mRNA vaccine arms (50 mcg dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+Delta, Omicron BA.1 monovalent, and Omicron BA.1+Prototype. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. Results: From March 30 to May 6, 2022, 597 participants were randomized and vaccinated. Median age was 53 years, and 20% had a prior SARS-CoV-2 infection. All vaccines were safe and well-tolerated. Day 15 geometric mean titers (GMT) against D614G were similar across arms and ages, and higher with prior infection. For uninfected participants, Day 15 Omicron BA.1 GMTs were similar across Omicron-containing vaccine arms (3724-4561) and higher than Prototype (1,997 [95%CI:1,482-2,692]). The Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. A subset of samples from uninfected participants in four arms were also tested in a different laboratory at Day 15 for neutralizing antibody titers to D614G and Omicron subvariants BA.1, BA.2.12.2 and BA.4/BA.5. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218-4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907). Conclusions: Higher Omicron BA.1 titers were observed with Omicron-containing vaccines compared to Prototype vaccine and titers against Omicron BA.4/BA.5 were lower than against BA.1 for all candidate vaccines. Clinicaltrials.gov: NCT05289037

Predicting the efficacy of variant-modified COVID-19 vaccine boosters

“…Secondly, if switching to a variantmodified vaccine, how important is it that the immunogen in the variant-modified vaccine is antigenically closely related to the spike protein of the circulating variant? We analysed the data from 8 reports that included a direct comparison of immunogenicity of an ancestralbased vaccine with a variant-modified vaccine [1][2][3][4][5][6][7][8] . They included data from the Sanofi-GlaxoSmithKline, Moderna, and Pfizer-BioNTech vaccine constructs incorporating the Beta, Delta, or Omicron BA.1 spike proteins (either alone or in combination with each other or the ancestral variant spike proteins).…”

Safety and immunogenicity of a broad-spectrum mosaic vaccine as a booster dose against SARS-CoV-2 Omicron and other circulating variants

“…18 Even within the Omicron variant, BA.4/BA.5 sub-variants also largely evaded the neutralization induced by BA.1 infection or vaccination, with a 2.6-8.0-fold drop in the nAb titers. [19][20][21] Therefore, there is an urgent need to develop broad-spectrum vaccines to fight against immune-evasive variants.…”

“…Utilizing the inactivated virus-based, mRNA-based, and recombinant protein-based platforms, multiple updated vaccines specific to Beta, Delta, Omicron BA.1 or Omicron BA.2 have been developed. 20,[22][23][24][25][26][27][28] Results of animal studies and clinical trials have shown that these variant-targeting vaccines could induce higher nAb responses than the ancestral vaccine against these specific variants. Furthermore, variant-specific vaccines along with prototype vaccines have been used in combination to achieve cross-neutralizing responses against divergent SARS-CoV-2 strains (ClinicalTrials.gov identifier: NCT05365724, NCT05381350, NCT05382871).…”

“…Furthermore, variant-specific vaccines along with prototype vaccines have been used in combination to achieve cross-neutralizing responses against divergent SARS-CoV-2 strains (ClinicalTrials.gov identifier: NCT05365724, NCT05381350, NCT05382871). 20,23,26,28 We, alternatively, adopt a new strategy on the principle of mosaic-type antigen for vaccine development to enable broad neutralization against SARS-CoV-2 variants. This strategy has been successfully applied in development of broad-spectrum vaccine against other highly mutated viruses, such as HIV and influenza, [29][30][31][32][33] and several studies indicated that the mosaic antigen could elicit broader antibody responses than those induced by the mixture of the corresponding monovalent antigens.…”

Neutralizing Antibody to Omicron BA.1, BA.2 and BA.5 in COVID-19 Patients

“…This has led to the recommendation by the FDA for including the Omicron variant in COVID-19 vaccines (4). However, issues have been raised about the value of adding Omicron to the vaccine based on data showing only modest differences between antibody responses after booster immunization with Omicron versus WA1 (5-7). Questions also remain about which Omicron variant(s) should be used and whether the WA1 strain should still be kept in the updated vaccine.…”