Omicron is associated with a marked ability of reinfection or breakthrough infection even in populations with wide vaccine coverage, benefiting from its heavily altered antigenicity 1,18. Since the identification of the variant, evidence prompted the need for developing Omicron-specific vaccines 7. Recent Omicron sublineages, BA.4/5, are currently causing most cases of COVID-19 in many countries, and have been shown to resist even more than BA.1 and BA.2 against neutralisation by triple-dosed vaccinee serums 19. It is evident that protection against symptomatic BA.4/5 reinfection in those with a previous pre-omicron SARS-CoV-2 infection was 35.5%, while in those with a history of infection with a post-Omicron subvariant (including BA.1 or BA.2), the protection was 76.2% 20. This highlights the role of prior exposure to Omicron subvariants in having high protection against the BA.4/5 21. The BQ and XBB subvariants, which are now rapidly expanding, are shown to further compromise the efficacy of current COVID-19 vaccines. The three shots of the ancestral-based vaccine showed far lower neutralization titers against BQ.1, BQ.1.1, XBB, and XBB.1 compared to the ancestral strain, with reductions of > 37-fold to > 71-fold. The variants also showed alarmingly high resistance to neutralization by serum of persons recently boosted with the new bivalent (covering BA.5) mRNA vaccines 22. Nonetheless, CDC data showed bivalent booster doses provided 73% additional protection against COVID-19 hospitalization compared to the ancestral-based monovalent vaccine through September-November 2022 when BQ.1 was circulating in the US 23.
To date (as of January 21, 2023), more than 13.2 billion doses of vaccine have been delivered to people, and 5.52 billion people, i.e. 69.3% of the global population, received at least one dose of COVID-19 vaccine (Our World in Data; Coronavirus (COVID-19) Vaccinations). However, almost all those vaccines were designed based on the antigens from the ancestral virus. In this study, we showed that even three doses of the ancestral-based vaccine could neutralise Omicron with a geometric mean titer of 27.9; whereas, three doses of the Omicron-based vaccine can result in 12-fold higher titer. This was in line with our previous pilot animal study in the mice model to evaluate the neutralization potency of the Omicron-specific vaccine, BIV1-CovIran, against Omicron variant, which its outline are presented in supplementary material (Supplementary material S1). We also showed delivering the third dose of the Omicron-based booster instead of repeating an ancestral-based booster dose can result in a 2- folds higher neutralisation titer (geometric mean of 27.9 vs. 64). Considering that Omicron and its sublineages may become the persistent variants that humans might face even when the pandemic ends 24, this study overwhelmingly recommends including an omicron component in COVID-19 booster vaccines. Updating current vaccines would shape immune antigenic memory to have the lowest antigenic distance to the current circulating SARS-CoV-2 subvariants, and makes the immune system responses compatible with the circulating epitopes. The updated vaccines could also be applicable in immunologically naïve populations, such as children who reach the age of eligibility for getting COVID-19 vaccines 6.
On the other hand, viral evolution continues and escape variants emerge, vaccine neutralization potency against multiple variants is highly desirable 8. In this study, the bivalent vaccine, without sacrificing potency against the Wuhan variant, achieved significantly higher neutralising titers against Omicron than the ancestral-based vaccine. Two doses of 5 µg bivalent vaccine (2.5 µg each) neutralised both Omicron and Wuhan variants by the geometric mean titer of 97. Interestingly, the titer against Omicron equals the titer elicited by two doses of the Omicron-based vaccine and is 13-fold higher than the titer elicited by two doses of the Wuhan-based vaccine. Delivering the third dose of bivalent vaccine increased the titer by more than 2-folds for both Omicron and Wuhan variants. Moreover, delivering the 10 µg bivalent vaccine (5 µg each) resulted in even higher neutralisation titers against Omicron and Wuhan variants in both two-dose and three-dose regimens. The broad neutralising antibody response shown in this study is in accordance with findings from bivalent vaccine boosters of Moderna in preclinical studies 25. The bivalent Omicron-containing vaccine candidate of Moderna not only elicited higher spike-binding antibody responses against omicron BA.1 than mRNA-1273 (based on ancestral strain) but also showed a superior response against BA.4/5 subvariants and ancestral Wuhan-1 variant. Mechanisms underlying the increased antibody responses with bivalent vaccines have yet to be elucidated but may include generating new memory immune responses 26.
This study is subjected to some limitations. First, the study evaluated neutralization titers against the Wuhan-Hu-1 and BA.1 sublineage; but the neutralization potency of the vaccines against BA.2, BQ.1, and XBB.1 subvariants remained unexplored. However, the prospering preclinical and real-world results of the Wuhan variant-based (BIV1-CovIran) against pre-Omicron variants, combined with the high anti-Omicron neutralization titers elicited by the Omicron-based vaccine (BIV1-CovIran Plus), would be a promise that the bivalent candidate may enhance immunity against all currently circulating variants 11,13. As the second limitation, non-neutralizing antibodies and cross-reactive T-cell responses, both of which could influence protective immunity, were not taken into account in our analysis 27. Future experiments using other circulating and emerging strains and evaluating other components of immune system may be informative to determine the breadth of the vaccine protection.
Immunity induced by existing COVID-19 vaccines is subjected to waning over time 28,29, which in the case of the Omicron is particularly concerning since it is coupled with the variant's ability to escape the humoral immune response elicited by ancestral variant-based vaccines 30,31. Altogether, the study iterate that the population’s waning immunity against SARS-CoV-2 should be recovered using Omicron-specific vaccines. This is especially important for Iran's case, in which the new peak of COVID-19 caused by BA.2, BQ.1, and XBB was officially declared by the ministry of health on December 30, 2022 32. Our findings indicate that Omicron-specific and bivalent vaccines may be a new tool in response to emerging variants, conserving neutralisation potency against Omicron sublineages. Accordingly, we are planning to evaluate the Omicron-based and bivalent vaccines according to the latest FDA guidance on the emergency use authorization for COVID-19 vaccines 33.