The identification of the Omicron variant (B.1.1.529) in South Africa in November 2021 -- featuring an extensive set of 30 mutations in the spike protein alone, including 15 in the neutralizing antibody targeting receptor binding domain (RBD) -- raises the question of whether Omicron merits its own variant-specific spike vaccine. While data are accumulating, early indications suggest we may not need one to weather the current Omicron wave. However, given the breadth of genetic changes and divergence from prior strains, it could be a useful variant to include as part of a next generation SARS-CoV-2 vaccine.
Are Current Boosters Protective Against the Variants?
Fortunately, while extremely infectious, the Omicron variant appears to be less pathogenic than Alpha, Beta, or Delta. While multiple clinical reports from South Africa support this, it isn't yet clear whether the reduced clinical severity is due to a high background rate of pre-existing immunity (with over 73% prior infection rate and a 31% vaccination rate) or reduced virulence. On a positive front, preclinical studies suggest less lower respiratory tropism, and potentially lower risk for characteristic COVID-19 lung injury. At this time, however, given the extremely high force of infection and the number of unvaccinated people in the U.S., we believe an aggressive boosting approach is warranted.
It is important to note that so far, the boosters in clinical use have the same SARS-CoV-2 spike protein sequence as the original strain from the beginning of the pandemic. Early indications suggest these boosters induce Omicron-specific neutralizing antibodies at levels that appear to be protective. Nevertheless, as with Beta and Delta, both Moderna and Pfizer/BioNTech are pursuing development of and clinical trials for an Omicron-specific spike vaccine. While earlier variant vaccines look safe and immunogenic, they are only marginally more potent against their targeted variants than an ancestral strain boost, thus raising the possibility that any marginal improvement from an Omicron vaccine may not be necessary.
How Have the Ancestral Strain Boosts Fared Against Omicron?
A press release from Moderna provided an update with respect to titers against Omicron specifically. Participants who had already received two doses of the Moderna vaccine were given a third dose of the original vaccine at either 50 µg (as currently deployed) or 100 µg; their titers against Omicron increased an average of 37-fold or 83-fold versus pre-boost levels. Participants who received a vaccine that consisted of a 1:1 mix of original and Beta (at either 50 µg or 100 µg) or a vaccine consisting of Beta + Delta (100 µg only) had a similar increase in Omicron-specific neutralization.
This suggests variant-specific boosters may have an advantage in eliciting variant-specific antibodies, but this advantage may not translate into meaningful clinical differences with current circulating variants and is likely to be offset by other factors.
Are Variant-Specific Boosters Worth the Investment?
To test, develop, and deploy variant-specific boosters would mean redirecting current vaccine manufacturing capacity, as well as complicating the logistics of shipping and administering vaccines on a global scale. Additional support from federal funding agencies and philanthropic organizations to continue to build vaccine infrastructure, including pilot lot manufacturing for rapid clinical trials, should be considered a public health priority. As the events of the last 2 years have shown, vaccine infrastructure should be considered an investment for the future.
It is also important to note that other arms of the immune system, particularly T cell-mediated elimination of infected cells, are likely to play a role in blunting the severity of disease in people who do have breakthrough infections. Unfortunately, numerous studies have shown that antibody levels decline relatively quickly after infection with SARS-CoV-2, which reinforces recommendations that people who have recovered from COVID-19 should also be vaccinated and boosted. Cytotoxic T cells responsive to a broad spectrum of strains may be important in filling this gap by quickly attenuating early infection when the neutralizing antibody response has waned.
Other Considerations
As SARS-CoV-2 is likely to continue to evolve, even if current vaccines provide adequate protection against emerging variants, future variants could be more challenging. Another concern is the emergence of an unrelated coronavirus with pandemic potential. To counter this, the NIH is supporting research and development of pan-coronavirus vaccines. Several different approaches are being assessed, including targeting conserved regions of the spike protein (receptor binding domain (RBD), N-terminal domain (NTD), and S2 region) and conserved cytotoxic T-cell epitopes. These immune targets are being tested as mosaic antigens, in multivalent configurations, and with novel delivery systems (e.g., protein nanoparticles or in virus like particles) that present the antigens to the immune system in ways that may improve cross-recognition. While some of these appear promising in animal models, clinical trials need to be conducted, and expediting these studies, as well as extending the correlates of protection analyses to serve as a benchmark for future COVID-19 vaccines, should be high priorities.
In summary, given the degree of genetic variance, we believe it is important to generate Omicron-specific vaccines for early phase testing. However, with the rapid spread of this strain throughout the world and the apparent benefit from current boosts, an Omicron-specific vaccine is unlikely to be necessary (or ready) for widespread use during this wave. The good news is boosted titers appear adequate to protect most individuals from severe disease within several months of their dose. So, public health efforts should continue to focus on boosting high-risk individuals with current vaccines now. Meanwhile, promising pan-sarbecovirus approaches that can induce both high levels of cross-neutralizing antibody and broad T-cell responses need robust support. Whether generation of an Omicron variant vaccine pays off in the future -- perhaps as part of a multivalent (flu-like) vaccine -- is unclear, but continuing vaccine development is wise given that it is the most successfully spreading and most divergent variant to date.
Troy Martin, MD, MPH, is Chief of Staff of the HIV Vaccine Trials Network (HVTN) and COVID-19 Prevention Trials Network (CoVPN) at Fred Hutchinson Cancer Research Center. Stephen R. Walsh, MDCM, is an Assistant Professor at Harvard Medical School and Brigham & Women's Hospital.
Disclosures
Martin disclosed NIAID funding for CoVPN activities. Walsh disclosed funding from NIAID and BARDA for CoVPN activities. He is also a co-investigator on Moderna CoVPN 3001/P301/COVE; co-investigator on Janssen/J&J CoVPN 3003/COV3001/ENSEMBLE; site PI for Sanofi VAT0002; site PI for Moderna P205; and Protocol Co-Chair for Sanofi CoVPN 3005/VAT0008.
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