Examining the uncertainties about value of including Omicron antigen in fall COVID-19 boosters

Both Moderna and Pfizer have already begun producing bivalent BA.1 boosters anticipated to be ready for this fall.1 Moderna Canada submitted its bivalent booster candidate (listed as elasomeran, imelasomeran; also known as mRNA-1273.214) to Health Canada on June 30 for regulatory approval.(2-4) The vaccine is a 50 µg dose that contains the original vaccine (Spikevax) and a vaccine candidate that targets Omicron BA.1. Pfizer Canada is also actively having discussions with Health Canada regarding submission of data for vaccines that include Omicron BA.1 or BA.4/5 subvariants.2 Read: Non-diabetics can have more complications from surgery than diabetics Recently, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the U.S. Food and Drug Administration (FDA) voted 19 to 2 to recommend inclusion of a SARS-CoV-2 Omicron component for COVID-19 booster vaccines this fall. Data presented at the VRBPAC meeting involved investigational bivalent boosters that combine (monovalent) prototype vaccines with the spike protein of the original Omicron variant, BA.1.1 Shortly after the VRBPAC meeting, the FDA announced that manufacturers planning to further update their COVID-19 vaccines should add a spike protein component of the Omicron subvariants BA.4 and BA.5 to their prototype vaccines, and these bivalent boosters should be available for use beginning this fall. The preference for adding Omicron subvariants BA.4 and BA.5 to prototype vaccines took into consideration how quickly SARS-CoV-2 has been evolving. By July 2, BA.5 represented 53.6% of US circulating SARS-CoV-2 variants, while BA.4 represented 16.5%. On the other hand, BA.1, which had represented about one-third of circulating US variants on March 26, was undetectable by May 21.1 Now even established subvariants of Omicron such as BA.5 are under threat from newer versions of the strain, such as BA.2.75, named Centaurus.5 After the VRBPAC meeting, the FDA did not advise manufacturers to alter the composition of COVID-19 vaccines for primary vaccination, since a primary series with authorized COVID-19 vaccines still provides good protection against serious outcomes of COVID-19 caused by circulating strains of SARS-CoV-2.1 Both Moderna and Pfizer have indicated that their BA.1 bivalent vaccines generate higher neutralizing antibody titres against BA.1 than against BA.4 and BA.5. The companies will continue to collect data about their bivalent BA.1 boosters, while developing BA.4 and BA.5 boosters.1 Read: New guidance released on helping patients manage the specialty baby formula shortage Some experts have questioned the value of adding an Omicron antigen to fall booster shots, for several reasons:1,5 There is no compelling evidence that adding a new element to the prototype monovalent vaccines is going to increase vaccine effectiveness. The prototype vaccines, which contain components of only the index SARS-CoV-2 strain, have effectively protected against severe disease caused by every variant so far. Before changing the composition of COVID-19 boosters, the benefits have to be clear. The vaccine manufacturers should be required present data about the immunogenicity for BA.4 and BA.5 after a fourth dose of their prototype vaccines compared with after a fourth dose of their investigational bivalent BA.1 vaccines. To date, the companies have presented data comparing the prototype and experimental bivalent vaccines against BA.1, which was no longer circulating in the U.S. by late May. We cannot assume that data generated for an Omicron BA.1 vaccine can easily be extrapolated to BA.4 and BA.5. Data presented at the VRBPAC meeting showed that a fourth dose of a bivalent vaccine containing a BA.1 component produced only a modest increase in neutralizing antibodies, compared with a fourth dose of the prototype COVID-19 vaccine. The difference in antibody titres between the prototype and bivalent boosters may have been statistically significant, but not necessarily clinically significant. Does adding a BA.1 component translate to longer or better protection against symptomatic disease? Will using BA.4 or BA.5 (instead of BA.1) produce any different (better) results? The speed at which new subvariants of COVID-19 are emerging means new variant-specific vaccines could quickly lose their relevance. By fall, it’s likely that Omicron will be “in the rearview mirror.” Vaccine development should be focused on trying to increase the breadth of the immune response rather than trying to match the variants that may be circulating. To overcome waning COVID-19 vaccine efficacy and the need for frequent updated boosters, researchers are now aiming to develop a universal COVID-19 vaccine (possibly an intranasal vaccine) that would be effective against multiple types of coronaviruses and multiple variants, while also requiring fewer (if any) updates over time.2,6 Pfizer–BioNTech plans to start clinical trials for a universal COVID-19 vaccine candidate in the second half of 2022.6 In its June 29 interim guidance on planning for fall 2022 COVID-19 vaccine booster programs in Canada, the National Advisory Committee on Immunization (NACI) stated that it will continue to monitor the evidence in the coming months to provide recommendations on the type and timing of vaccines for subsequent booster doses.7 References 1. Rubin R. COVID-19 boosters this fall to include Omicron antigen, but questions remain about its value. JAMA 2022. Published online July 8, 2022. (accessed July 14, 2022). 2. Szklarski C. The next stage in the battle against COVID-19: bivalent vaccines. CTV News July 7, 2022. (accessed July 14, 2022). 3. Government of Canada. Drug and vaccine authorizations for COVID-19: list of applications received. (accessed July 14, 2022). 4. Moderna, Inc. Moderna’s Omicron-containing bivalent booster candidate, mrna-1273.214, demonstrates significantly higher neutralizing antibody response against Omicron subvariants BA.4/5 compared to currently authorized booster. July, 11, 2022. (accessed July 14, 2022). 5. Gordon N. An Omicron vaccine is coming. Should you wait for it—or get your next booster now amid BA.5’s surge? Fortune 2022; published July 12, 2022. (accessed July 14, 2022). 6. Lennon A. Pfizer and BioNTech to test universal COVID-19 vaccine candidate. Medical News Today July 7, 2022. (accessed July 14, 2022). 7. National Advisory Committee on Immunization (NACI). An Advisory Committee Statement (ACS). Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. Published: June 29, 2022. (accessed July 14, 2022)

Examining the uncertainties about value of including Omicron antigen in fall COVID-19 boosters

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