Shortening HIV vaccine regimens to achieve high coverage

An international commission of global experts convened by the International AIDS Society and The lancet in 2018 advised that to eliminate HIV, global treatment efforts should be complemented by a robust scale-up in primary HIV prevention, including the development of a preventive vaccine.¹ To date, only one HIV vaccine trial has shown moderate efficacy of the vaccine.² This trial done in Thailand used an ALVACHIV prime, followed by two boosts of ALVAC-HIV plus AIDSVAX B/E Alum adjuvanted protein. A follow-up trial (HVTN 702} done in South Africa that used an adapted HIV subtype C vaccine adjuvanted with MF-59 was recently discontinued in February, 2020, because of lack of efficacy, highlighting the need for novel vaccine approaches.

Modelling studies suggest that an HIV preventive vaccine with 70% efficacy and high uptake in adolescents and adults could reduce new infections by 65% in 25 years.³ Achieving this level of efficacy will probably require a multidose HIV vaccine, creating potential implementation challenges. In middle-income and low-income countries, because of inadequate infrastructures for routine immunisation of non-paediatric populations, achieving high vaccination coverage in adolescents and adults generally requires mass vaccination campaigns.⁴ Despite their high efficiency, mass vaccination approaches are costly and might not be suitable for extended multidose immunisation schedules. Simplified HIV immunisation regimens that could be administered over a short period and induce long-lasting protective immunity are therefore highly desirable.

In a phase 1/2a trial, the Ad26 vaccine with gp140 adjuvant was well tolerated and highly immunogenic in humans.⁵ In a parallel non-human primate study, this regimen afforded 67% protection from SHIV-SF162P3 intrarectal challenge.⁵ The ongoing phase 2b clinical trial lmbokodo (HVTN 705/HPX2008; NCT03060629) is evaluating the efficacy of this vaccine strategy, which consists of four vaccine doses administered over a 12-month period. Importantly, because the lmbokodo trial uses a vaccine strategy distinct from that used in the failed HVTN 702 trial, the results from one trial are not predictive of the other’s results. Should the results of the lmbokodo trial warrant consideration for licensure of the vaccine, the implementation of this yearlong multidose vaccination approach could be challenging. In The Lancet HIV, Kathryn E Stephenson and colleagues⁶ evaluated the immunogenicity of shortened and simplified Ad26 with gpl40 vaccine regimens. They showed that regimens consisting of three vaccine doses administered over a 6-month period induced peak immune responses comparable with the extended 12-month regimen. Moreover, after intrarectal challenge, rhesus monkeys immunised with a short vaccine regimen had a per-exposure infection risk reduction comparable with animals immunised with the extended regimen.

The relevance of vaccine efficacy in rhesus monkeys to protection in humans is uncertain, but the results of the study by Stephenson and colleagues⁶ raise cautious optimism that it could be possible to develop short, efficacious HIV immunisation regimens that are relatively easy to implement. Nevertheless, the potential effect on clinical efficacy of the subtle differences in the phenotype and durability of the vaccine-elicited immune responses observed between the vaccine groups in this small study (36 human participants) is unknown. Notably, it is unclear whether these differences contributed to the lower vaccine protection observed with the shortened regimen in non-human primates (40%} than the 67% protection previously observed with the extended regimen.⁴ In the moderately effective RV144 trial,⁷ the estimated vaccine efficacy significantly dropped between 6 months to 12 months after vaccination, which correlated with the rapid decrease of vaccine-induced antibody responses. This result highlights the importance of maintaining adequate concentrations of protective antibodies over time and warrant further optimisation of shortened vaccination regimens. Contrasting with the Ad26-plus-gp140 strategy that elicits only non-neutralising antibodies,^5,6 other vaccine approaches currently under development aim at inducing broadly neutralising antibodies. However, because broad neutralisation develops only after several years in a subset of infected individuals,⁸ short vaccine regimens might not be able to induce this type of response.

Importantly, although implementing extended multidose vaccine regimens in adult populations might present challenges, several multidose vaccines are routinely administered early in life. In most countries, adequate infrastructures are in place and paediatric vaccine coverage rates are high. Thus, early life could present important advantages for vaccines that require several doses. A scenario in which an initial multidose HIV immunisation series administered early in life is followed by boosting in pre-adolescence and adulthood (possibly through mass vaccination campaigns) could therefore afford high vaccine coverage rates. However, whether Ad26 plus gp140 or other immunisation approaches are able to elicit protective immune responses in infants that could be boosted later in life remains to be investigated.