More than 30 years since its discovery and there is still no FDA licensed HIV vaccine. It is not even entirely clear if the failure to develop effective HIV vaccine has really anything to do with frequent HIV antigenic shift. Flu virus, for example, also undergo quite frequent antigenic shift and still there is Flu vaccines with 60-90% efficacy.
New study published this week in journal Science suggested new explanation for frequent failure with HIV vaccine(s). It appears that cross-reactivity between gp41 component of HIV vaccine and endogenous microbiota antigen (component of E. coli RNA polymerase) prevented development of neutralizing gp120-specific antibody titre.
The authors have analysed Ab repertoire to HIV-1 DNA prime, recombinant Adenovirus Type 5 (rAd5) boost vaccine. They found that 93% of Env specific antibodies derived from sorted memory B cells were directed against non-neutralizing gp41 antigen.
Interestingly, majority of those gp41-specific antibodies utilized polyreactive, innate-like IGHV1-69 variable segment. VH1-69 locus is involved in Ab repertoire directed to Flu stem region. But unlike Flu specific VH1-69 Abs, gp41-specific VH1-69 Abs were made of allele variants with Leucine substitution at position 54 in HCDR2.
Finally, analysis of antigen specificity of individual gp41 mAbs revealed high level of polyreactivity towards commensal and self antigens.
In summary, these results points to the most important aspect of immune system, namely that strength and specificity of immune response is controlled by environmental antigens, including microflora antigens. It is my opinion that future vaccine testing would require incorporation of cross-reactivity tests against wide range of environmental antigens to select the most effective immunogens.