BA.1 breakthrough infection in vaccinated HCW induces low protection against BA.4 and BA.5 Omicron variants- unique protein expression profile and its possible clinical implications

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) have emerged during the pandemic. Omicron is now the dominant virus around the globe and has four main sub-variants: BA.1, BA.2, BA.4, and BA.5. These variants contain more than 30 mutations in their spike protein. They cause milder disease than previously VOC, but are highly transmissible and have decreased susceptibility to therapeutic monoclonal antibodies and to the exisiting vaccines. When compared with BA.2, the BA.4 and BA.5 sub-variants carry three additional mutations in their spike protein, which have raised concerns regarding their potential to evade neutralising antibodies, thereby further compromising the effectiveness of COVID-19 vaccines and therapeutic monoclonal antibodies. There is still limited information about whether individuals immunised with COVID-19 vaccine are protected against Omicron BA.4 and BA.5 compared with other strains. We monitored the frequency of SARS-CoV-2 variants in Israel by whole genome sequencing and describe the appearance of the Omicron variants in Israel. We also evaluated neutralising antibody titres against wild type (WT) and four Omicron variants (BA.1, BA.2, BA.4 and BA.5) in healthcare workers who had breakthrough BA.1 infection. Omicron breakthrough infection in individuals vaccinated three or four times before infection resulted in increased neutralising antibodies against the WT virus. The fourth vaccine dose did not further improve the neutralising efficiency over the third dose against all Omicron variants, especially BA.4 and BA.5. An Omicron-specific vaccine may be indicated.