Caveats of chimpanzee ChAdOx1 adenovirus-vectored vaccines to boost anti-SARS-CoV-2 protective immunity in mice

Abstract

Several COVID-19 vaccines use adenovirus vectors to deliver the SARS-CoV-2 spike (S) protein. Immunization with these vaccines promotes immunity against the S protein, but against also the adenovirus itself. This could interfere with the entry of the vaccine into the cell, reducing its efficacy. Herein, we evaluate the efficiency of an adenovirus-vectored vaccine (chimpanzee ChAdOx1 adenovirus, AZD1222) in boosting the specific immunity compared to that induced by a recombinant receptor-binding domain (RBD)-based vaccine without viral vector. Mice immunized with the AZD1222 human vaccine were given a booster 6 months later, with either the homologous vaccine or a recombinant vaccine based on RBD of the delta variant, which was prevalent at the start of this study. A significant increase in anti-RBD antibody levels was observed in rRBD-boosted mice (31–61%) compared to those receiving two doses of AZD1222 (0%). Significantly higher rates of PepMix™- or RBD-elicited proliferation were also observed in IFNγ-producing CD4 and CD8 cells from mice boosted with one or two doses of RBD, respectively. The lower efficiency of the ChAdOx1-S vaccine in boosting specific immunity could be the result of a pre-existing anti-vector immunity, induced by increased levels of anti-adenovirus antibodies found both in mice and humans. Taken together, these results point to the importance of avoiding the recurrent use of the same adenovirus vector in individuals with immunity and memory against them. It also illustrates the disadvantages of ChAdOx1 adenovirus-vectored vaccine with respect to recombinant protein vaccines, which can be used without restriction in vaccine-booster programs. Key points • ChAdOx1 adenovirus vaccine (AZD1222) may not be effective in boosting anti-SARS-CoV-2 immunity • A recombinant RBD protein vaccine is effective in boosting anti-SARS-CoV-2 immunity in mice • Antibodies elicited by the rRBD-delta vaccine persisted for up to 3 months in mice

The Immune System – Friend or Foe for Adenovirus Based Therapies?

“…This may be due to anti-vector immunity impeding the booster dose. The beneficial effect of heterologous vs homologous vaccine strategies is well established and could be attributed to anti-vector immunity [240,241]. The reduction of protection is shown to be even more pronounced when vaccine recipients were tested for anti-Ad antibodies prior to vaccination: In a trial for an Ad based Ebola vaccine in 2010, seronegative participants had a significantly better antigen specific immune response than those that were seropositive for HAdV-C5 [242].…”

“…Some groups have been successful in utilising nonhuman Ads, such as ChAds, bovine or porcine Ads. As they rare or even absent in the human population, there is less likelihood of specific immunity to whichever Ad was chosen [241,246]. Crossreactivity between different serotypes, especially when originally targeting different hosts, is also usually low [246,247].…”

The Immune System—A Double-Edged Sword for Adenovirus-Based Therapies

“…This may be due to anti-vector immunity impeding the booster dose. The beneficial effect of heterologous vs. homologous vaccine strategies is well established and could be attributed to anti-vector immunity [ 248 , 249 ]. The reduction in protection is shown to be even more pronounced when vaccine recipients were tested for anti-Ad antibodies prior to vaccination.…”

“…Some groups have been successful in utilising non-human Ads, such as ChAds, bovine, or porcine Ads. As they are rare or even absent in the human population, there is less likelihood of specific immunity to whichever Ad is chosen [ 249 , 254 ]. Cross-reactivity between different serotypes, especially when originally targeting different hosts, is also usually low [ 254 , 255 ].…”

Clinical development of SpikoGen®, an Advax-CpG55.2 adjuvanted recombinant spike protein vaccine

“… 8 Unfortunately, adenovirus vector vaccines were associated with high reactogenicity and some lethal thrombotic events and have now been taken off the market. 9 , 10 Similarly, mRNA vaccines were associated with high reactogenicity and inflammatory myocarditis, 11 provided relatively short-lived protection, required frequent boosters, 12 were expensive and were not stable except at very low temperatures. This indicates that these newer technologies are not ideal pandemic solutions.…”