Evidence for Env-V2 sieve effect in breakthrough SIV _MAC251 infections in rhesus monkeys vaccinated with Ad26/MVA and MVA/Ad26 constructs

Background

We had previously shown that rhesus monkeys receiving Ad26/MVA and MVA/Ad26 vaccines expressing SIV_SME543 were protected against SIV_MAC251 challenge (doi:10.1038/nature10766). Protection was associated with Env-specific binding ELISA antibody responses, including V2-specific antibodies.

Methods

We amplified 66 sequences from the SIV _MAC251 challenge stock, and 409 near-full length genomes from 13 vaccine and 13 control monkeys. A series of pre-specified phylogenetic and statistical tests for sieve effects was performed.

Results

The mean pairwise AA diversity among the 66 SIV_MAC251 Env sequences was 0.38%, and they differed from the vaccine strain SIV _SME543 (Env) by 21.94%. The repeated low-dose challenge resulted in infections with an average of 1.7 founder variants - with no evidence that the vaccine restricted the number of variants (p = 0.813). We explored whether the vaccine induced a sieve effect, i.e. whether breakthrough viruses differed between the vaccine and control groups. There was no difference for full-length Env sequences. Focusing on Env segments preferentially recognized by vaccinated monkeys in antibody arrays, we identified a sieve effect in the Env-V2 segment AA163-193: sequences from vaccinated animals were more divergent from the vaccine SIV_SME543 or from the challenge stock SIV_MAC251 than sequences in control animals (p ≤ 0.002).

Conclusion

The sieve effect in Env-V2, combined with Env-V2-specific binding antibodies identified as a correlate of protection against SIV _MAC251 acquisition in the study, provide evidence supporting the importance of protective responses directed against the Env-V2 region.