SARS-CoV-2 is a novel betacoronovirus that first appeared in late 2019 in Wuhan, China. It presented with pneumonia-like symptoms and infections ranged from mild to severe, requiring hospitalisation and medical intervention to prevent death. Due to a lack of previous immunity, SARS-CoV-2 spread around the globe at a rapid rate requiring the declaration of a pandemic and for countries to enforce national responses, such as widespread lockdowns and preventative measures including mask wearing and social distancing. Several vaccines were rapidly developed. These included BioNTech Pfizer’s BNT162b2 mRNA-based vaccine, Moderna’s mRNA-1273 mRNA-based vaccine, and Oxford AstraZeneca’s viral vectored AZD1222 vaccine. These were administered to the public in mass vaccination drives in two doses followed by a booster dose approximately six months later. Initially, the vaccines were administered to prevent infection but due to novel variants that arose, this later changed to preventing severe infection which may require hospitalisation.

Several novel variants arose with substitutions occurring in the spike glycoprotein. As the spike protein is used by the virus for viral entry, these substitutions may have evolved to increase entry efficiency of the virus into the host cells. These novel variants included B.1.1.7 (alpha), B.1.351 (beta), P1 (gamma), B.1.617.1 (kappa), B.1.617.2 (delta), and B.1.1.529 (omicron). These variants had mutations in the receptor binding domain (RBD) of the spike glycoprotein which altered its conformation, thereby evading previous immunity from natural infection or vaccination, and allowing for increased binding to the SARS-CoV-2 receptor ACE2 and increased entry efficiency. This was hypothesised to cause increased transmission of the novel variants, requiring increased public health measures to prevent the spread of SARS-CoV-2, particularly in vulnerable populations, such as the elderly.

The elderly population (≥80 vaccinated with BNT162b2 and an mRNA booster, and ≥70 vaccinated with two doses of AZD1222 and an mRNA booster) were determined to be a vulnerable population due to immunosenescence, which resulted in lower spike-specific antibody binding titres, lower neutralising antibody titres against spike pseudotyped viruses, lower T cell interferon gamma (IFNγ) and interleukin-2 (IL-2) responses, and reduced spike-specific memory B cell populations. In the population vaccinated with BNT162b2, these effects were reduced with the second vaccination dose and whilst responses waned over six months post vaccination, they were rescued with the booster vaccination dose, indicating a durable T and memory B cell response.

Individuals primed with two doses of AZD1222 and boosted with an mRNA vaccine had lower neutralising antibody titres after two doses compared with individuals vaccinated with BNT162b2. However, this was rescued with the mRNA booster. Interestingly, a subset of atypical memory B cells which have been associated with aging were identified in the ≥70 population, indicating a mechanism for persistent immunity to form. This also conferred protection against novel variants of concern, such as B.1.1.529, which individuals were not able to sufficiently neutralise after two doses of AZD1222 coupled with waning immunity over six months post vaccination.

These findings contribute to the understanding of entry efficiency of SARS-CoV-2 variants, which may be a reason for increased transmission and how this impacts immunity, particularly in the elderly. This will inform vaccination policies, particularly in the vulnerable and elderly populations, leading to greater immune protection against SARS-CoV-2 and possible future variants of concern that may arise.