Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines

Abstract

The optimal vaccination strategy to boost responses in the context of pre-existing immune memory to the SARS-CoV-2 spike (S) glycoprotein is an important question for global public health. To address this, we explored the SARS-CoV-2-specific humoral and cellular immune responses to a novel self-amplifying RNA (saRNA) vaccine followed by a UK authorised mRNA vaccine (BNT162b2) in individuals with and without previous COVID-19, and compared these responses with those who received an authorised vaccine alone. 35 subjects receiving saRNA (saRNA group) as part of the COVAC1 clinical trial and an additional 40 participants receiving an authorised SARS-CoV-2 vaccine only (non-saRNA group) were recruited. Antibody responses were measured by ELISA and a pseudoneutralisation assay for wildtype, Delta and Omicron variants. Cellular responses were measured by IFN-ƴ ELISpot and an activation induced marker (AIM) assay. Approximately 50% in each group had previous COVID-19 prior to vaccination, confirmed by PCR or antibody positivity on ELISA. All of those who received saRNA subsequently received a full course of an authorised vaccine. The majority (83%) of those receiving saRNA who were COVID-19 naïve at baseline seroconverted following the second dose, and those with previous COVID-19 had an increase in antibody titres two weeks following saRNA vaccination (median 27-fold), however titres were lower when compared to mRNA vaccination. Two weeks following the 2nd authorised mRNA vaccine dose, binding and neutralising antibody titres were significantly higher in the saRNA participants with previous COVID-19, compared to non-saRNA, or COVID-19 naive saRNA participants. Cellular responses were again highest in this group, with a higher proportion of spike specific CD8+ than CD4+ T cells when compared to those receiving the mRNA vaccine only. These findings suggest an immunological benefit of increased antigen exposure, both from natural infection and vaccination, particularly evident in those receiving heterologous vaccination with saRNA and mRNA.

Antibodies from dengue patients with prior exposure to Japanese encephalitis virus are broadly neutralizing against Zika virus

“…Similarly, the mice study with sequential WNV and JEV exposures suggests that flavivirus-specific MBCs bypass the germinal center in recall response, whose activity depends on the initial clonal diversity of MBCs derived from the initially encountered antigens 55 . Other factors, such as the interval of priming and boosting, the order of heterologous exposures, or the types of antigens used and the duration after the germinal center formation before encountering heterologous antigens could also complicate the outcome of heterologous immunity 56 , 57 . Further experimental work is needed to determine whether prime-boost immunization of heterologous antigens in mice could also induce similar clonally diverse MBCs in the context of flavivirus infections.…”

A phase I/II clinical trial of intradermal, controllable self-replicating RNA vaccine EXG-5003 against SARS-CoV-2

“…Blood sampling of BNT162b2 vaccine groups occurred before vaccination (BNT162b2 [pre]), 2 weeks after the first vaccination (BNT162b2 [1 dose]), and 2 weeks after the second vaccination (BNT162b2 [2 doses]) (Table S6). Two weeks after the vaccination is considered the time for peak cellular immunity 11,12,25,26 .…”

Self-Amplifying RNA: A Second Revolution of mRNA Vaccines against COVID-19

“…Surprisingly, there were no significant differences in humoral or cellular responses between groups. However, upon categorizing participants based on prior COVID-19 status, the researchers noted that two weeks after the second dose of the mRNA vaccine, nAb titers were notably higher among saRNA recipients with a history of COVID-19 compared to those who received homologous mRNA vaccination or COVID-19-naive saRNA recipients [ 110 ]. These findings suggest that increased antigen exposure, whether from natural infection or vaccination, may confer immunological advantages that are particularly evident in individuals undergoing heterologous vaccination.…”