SARS-CoV-2 S2–targeted vaccination elicits broadly neutralizing antibodies

Abstract

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S–targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan–based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.

Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

“…This was not exactly the case in our study, indicating that in addition to imprinted memory, responses targeting novel antigens can be generated. Besides the RBD, antibodies targeting other regions of the spike, such as the NTD or S2 region may also broaden the humoral response 60,61 . The interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses 62 .…”

A variant-proof SARS-CoV-2 vaccine targeting HR1 domain in S2 subunit of spike protein

“…However, there has been no report so far about the clinical or per-clinical studies on SARS-CoV-2 vaccines targeting the S2 subunit, although Ng et al has reported that a DNA vaccine containing genes encoding membrane-bound SARS-CoV-2 S2 subunit can induce bnAbs against sarbecoviruses, while the bacterially produced recombinant S2 protein cannot elicit bnAbs. 85 These results, together with those from our study, suggest that these S2-specific bnAbs isolated from the SARS-CoV-2-infected or vaccinated individuals may be elicited by the neutralizing epitopes in the conserved regions of S2 subunit at a special fusion conformation (e.g., prefusion, fusion intermediate or post-fusion conformation), while our HR121 vaccine can induce potent bnAb responses in the vaccinated animals, possibly because HR121 vaccine contains the transiently exposed neutralizing epitopes in the HR1 region of S2 subunit present in the fusion intermediate conformation. Therefore, it is both a great opportunity and a challenge to design an effective S2 subunit vaccine containing the exposed neutralizing epitopes in the conserved regions of S2 subunit at a proper conformation that can induce potent and broad-spectrum cross-nAb responses.…”

What next for covid-19 vaccines?: Video 1

“…In a paper published in Science Translational Medicine in July the team reported that mice had created antibodies able to neutralise other animal and human coronaviruses, including the seasonal "common cold," the alpha, beta, and delta variants, the original omicron variants, and two bat coronaviruses. 10 And DIOSynVax, a biotech spinout from the University of Cambridge, is developing an mRNA vaccine that could protect against a number of coronaviruses including SARS-CoV-1, SARS-CoV-2, and MERS. In March it received a $42m (£38m; €43m) award from the Coalition for Epidemic Preparedness Innovations.…”

“…Another team, based at the Francis Crick Institute in the UK, is in the early stages of testing a candidate targeting a specific area of the spike protein known as the S2 subunit, which allows the virus to fuse with the host cell. In a paper published in Science Translational Medicine in July the team reported that mice had created antibodies able to neutralise other animal and human coronaviruses, including the seasonal “common cold,” the alpha, beta, and delta variants, the original omicron variants, and two bat coronaviruses 10…”