Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

(Page numbers not final at time of first release) 2 adenovirus 26/5 for prime/boost). Novavax NVX-CoV2373 is a prefusion-stabilized S protein-subunit vaccine formulated with a saponin-based matrix M adjuvant whereas Sinopharm BBIBP-CorV comprises inactivated virions. The primary vaccine series consisted of two doses for all of these vaccines except for Ad26.COV2.S which was administered as a single dose.
We first aimed to understand how the different S mutations in the Omicron variant sublineages impact host receptor engagement and membrane fusion. Whereas the Delta RBD recognized human ACE2 with a comparable affinity to that of the Wuhan-Hu-1 RBD (1.1-fold enhancement by biolayer interferometry (BLI) (3) and 1.5-fold enhancement by surface plasmon resonance (SPR)), the ACE2-binding affinity was greater for the BA.1 RBD (4.4-fold by BLI and 2.6-fold by SPR) (4,12,15) and for the BA.2 RBD (3.7-fold by BLI, 2.3-fold by SPR) (Fig. 1, D and E; figs. S1 and S2; and tables S1 and S2). The BA.2.12.1 RBD, which differs from the BA.2 RBD only by the L452Q mutation, had an ACE2-binding affinity similar to the Wuhan-Hu-1 RBD (1.1-fold and 1.7-fold enhancements determined by BLI and SPR, respectively). The ACE2-binding affinity of the BA.4/5 RBD was the greatest among the RBDs evaluated here with 6.1-fold and 4.2-fold increases relative to Wuhan-Hu-1, as determined by BLI and SPR, respectively (Fig. 1, D and E; figs. S1 and S2; and tables S1 and S2).
Here we report that the BA.1, BA.2, BA.2.12.1, and BA.4/5 Omicron sublineages, which account for over 99% of all infections worldwide over the first half of 2022, have increased ACE2 binding affinity, decreased fusogenicity and markedly evade neutralizing antibody responses relative to the Wuhan-Hu-1 and Delta strains (3). Collectively, these data suggest that enhanced receptor engagement and immune evasion are key changes that may have promoted the rapid spread of these Omicron sublineages and could contribute to the current rise in prevalence of BA.4 and BA.5.
The development of life-saving vaccines is regarded as one of humanity's greatest medical and scientific achievements, which is exemplified by COVID-19 vaccines (52)(53)(54). Primary COVID-19 vaccine regimens or infection-elicited plasma neutralizing activity was severely dampened by Omicron sublineages BA.1, BA.2, BA.2.12.1, and BA.4/5. However, administration of a booster dose increased neutralizing antibody titers and breadth against all Omicron sublineages to appreciable levels regardless of the vaccine evaluated, concurring with findings for BA.1 (5,12,15,17,49,55,56). These results are consistent with previous studies demonstrating that a third vaccine dose results in the recall and expansion of pre-existing SARS-CoV-2 S-specific memory B cells, as well as de novo induction, leading to production of neutralizing antibodies with enhanced potency and breadth against variants (57,58). Vaccinees receiving two doses of Ad26.COV2.S (four months apart) had lesser Omicron immune escape than other two dose vaccine recipients (three to four weeks between doses) but greater than three dose vaccinees. These findings suggest that the time interval between immunizations may affect the breadth and potency of vaccine-elicited plasma neutralizing activity, and that a third dose may be beneficial for this cohort as well (59)(60)(61)(62). Moreover, the induction by several currently available vaccines of robust cross-reactive cellular immunity against SARS-CoV-2 Omicron is likely playing a key role in the retained protection observed against severe disease (63,64).
As SARS-CoV-2 progressively becomes endemic in the human population, vaccination strategies will need to be carefully considered and optimized to provide long-lasting immunity. So far, elicitation of high titers of variant-neutralizing antibodies and protection against severe disease can be accomplished by dosing with the Wuhan-Hu-1 S antigen, as shown in animal models and studies of vaccine efficacy in humans (5,48,65,66). In fact, an Omicron BA.1 (or other variant) S boost does not offer mice or non-human primates significantly more BA.1 protection than a Wuhan-Hu-1 S boost (67)(68)(69)(70)(71), and Omicron primary infections elicit neutralizing antibody and memory responses of narrow breadth (72-74). However, continued SARS-CoV-2 evolution will accentuate the antigenic divergence from the ancestral strain and it is unknown if vaccines based on Wuhan-Hu-1 S alone will provide satisfactory protection, either as boosters in vaccinated or infected individuals or as an initial vaccine in naive individuals (mainly children). The recent evaluation of intranasal vaccine administration could also be important to not only prevent severe disease but also curtail viral infection and transmission through induction of mucosal immunity (75)(76)(77)(78). For these reasons, it is important to monitor new variants, assess the effectiveness of currently available vaccines, and continue to test and implement new vaccination strategies that may provide stronger, longer lasting, or broader protection against SARS-CoV-2 and the entire sarbecovirus subgenus (40,79,80