A human immunodeficiency virus (HIV) vaccine is of high importance for the control of the current pandemic. Outside of screening blood, male circumcision and drug treatment of mothers and infants at birth, the effectiveness of public health measures have been limited by compliance and cost. Particularly important in the path towards an HIV vaccine has been the Thai RV144 efficacy trials, which demonstrated that priming with a recombinant canary poxvirus (ALVAC) and boosting with ALVAC plus gp120 protein provided partial protection against HIV. In RV144, a non-neutralizing antibody was associated with reduced risk. Non-neutralizing antibodies, which can directly block infection, distinguish themselves from neutralizing antibodies by mediating protection via the fragment crystallizable (Fc) regions of bound antibody, triggering killing by innate immune responses, such as antibody-dependent cellular cytotoxicity, phagocytosis and complement-mediated killing.
GeoVax (Atlanta, GA, USA) has developed clade B vaccines that have undergone phase I and IIa clinical testing in the Americas through the HIV Vaccine Trials Network. These vaccines have tested priming with a recombinant DNA vaccine that expresses virus-like particles (VLPs) and boosting with a recombinant modified vaccinia Ankara (MVA) (an attenuated smallpox vaccine) that also expresses VLPs, as well as the simpler regimen of priming and boosting with the VLP-expressing recombinant MVA vaccine (Figure 1). The vaccine has shown excellent safety and consistent immunogenicity in clinical trials where two DNA primes followed by two MVA boosts and a single MVA prime followed by two MVA boosts have been evaluated. Both regimens have elicited Env-specific antibodies in, essentially, 100% of participants. For both regimens, antibody responses target both the gp120 receptor binding and gp41 transmembrane subunits of Env, but are biased towards gp41. For both, Env-specific antibodies are predominantly IgG1 (> 90%) and IgG3 (∼75%) with low response rates of serum IgA (∼20%), an isotype profile favourable for protective non-neutralizing antibodies. The antibody to gp41 includes responses to the immunodominant region of gp41 (77–81% positive), a highly conserved target for antibody-dependent cellular cytotoxicity (ADCC) and virion capture. For both regimens, the gp41 antibody, including that to the immunodominant region, has exhibited excellent longevity, declining by less than threefold in the 6 months post immunization. Functional studies of antibodies reveal high rates of ADCC in bound virion (85.7% response rate) and bound gp120 (64.3% response rate) assays. Response rates for tier 1 and tier 2 neutralizing antibodies have ranged from undetectable to 60%. The value of adding a gp120 protein boost to the DNA priming and MVA boosting, as well as the MVA-only regimen, is currently being evaluated, following which a regimen will be selected for advancement into phase IIb efficacy testing in homosexual men in the Americas.