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BackgroundPatients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity.ObjectivesTo determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency.MethodsParticipants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays.ResultsFollowing a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%).ConclusionThese data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.