This is a summary, written by members of the CITF Secretariat, of:

Grant MD, Bentley K, Fielding CA, Hatfield KM, Ings DP, Harnum D, Wang E, Stanton R, Holder KA. Anti-S1 and S2 antibodies from hybrid immunity elicit potent cross-variant ADCC against SARS-CoV-2. JCI Insight. June 20 2023. DOI:

The results and/or conclusions contained in the research do not necessarily reflect the views of all CITF members.

A CITF-funded study, published in JCI Insight, showed that hybrid immunity (resulting from having both an infection and vaccination) confers greater protection against cell-to-cell spread of SARS-CoV-2 than vaccination alone. This might explain why hybrid immunity offers better protection against reinfections than vaccination alone. The study was led by Dr. Kayla Holder (Memorial University of Newfoundland) in collaboration with Dr. Michal Grant (Memorial University of Newfoundland) and Dr. Richard Stanton (Cardiff University, United Kingdom). Based on their results, the researchers argue that COVID-19 vaccines should not focus solely on inducing anti-RBD antibody responses, but rather on a combination of S1- and S2-specific antibody responses.

Current COVID-19 vaccines are very effective at inducing potent neutralizing antibodies that prevent the circulating SARS-CoV-2 virus from entering uninfected cells, which is critical for reducing viral replication. Other types of antibodies are involved in counteracting cell-to-cell transmission. Those antibodies recognize infected cells by viral markers on their surface and recruit other cells from the immune system, such as natural killer (NK) cells, to kill the infected cells through a mechanism called antibody-dependent cellular cytotoxicity (ADCC). ADCC is key to controlling the virus.

Key findings:

  • COVID-19 vaccine-induced antibodies induced weak ADCC. Among the reasons for this is that vaccination primarily induces antibodies targeting the S1 domain of the spike protein.
  • Antibodies from individuals with hybrid immunity elicited significantly greater cytotoxicity. Infection, in particular, promoted the production of antibodies against the S2 domain of the spike protein. Thus, hybrid immunity boosted antibody responses against both S1 and S2.
  • This capacity of hybrid immunity to kill infected cells through ADCC was maintained against new variants of concern, including Delta and Omicron, which are known to escape neutralizing antibodies.

Most COVID-19 vaccines used today are based on the ancestral spike (S) protein of the SARS-CoV-2 virus, thereby inducing anti-S antibodies. More precisely, the major focus has been on inducing antibodies targeting the receptor binding domain (RBD) found on the S1 domain of the S protein. These anti-RBD, vaccine-induced antibodies are capable of neutralizing cell-free viruses by blocking them from infecting cells. However, new SARS-CoV-2 variants have been able to escape the neutralizing activity of vaccine-induced antibodies by reducing their ability to bind. This study suggests that spike-only subunit vaccines would benefit from strategies to induce a combination of S1- and S2-specific antibody responses.