Are Clade Specific HIV Vaccines a Necessity? An Analysis Based on Mathematical Models

Abstract

As HIV-1 envelope immune responses are critical to vaccine related protection, most candidate HIV vaccines entering efficacy trials are based upon a clade specific design. This need for clade specific vaccine prototypes markedly reduces the implementation of potentially effective HIV vaccines. We utilized a mathematical model to determine the effectiveness of immediate roll-out of a non-clade matched vaccine with reduced efficacy compared to constructing clade specific vaccines, which would take considerable time to manufacture and test in safety and efficacy trials. We simulated the HIV epidemic in San Francisco (SF) and South Africa (SA) and projected effectiveness of three vaccination strategies: i) immediate intervention with a 20-40% vaccine efficacy (VE) non-matched vaccine, ii) delayed intervention by developing a 50% VE clade-specific vaccine, and iii) immediate intervention with a non-matched vaccine replaced by a clade-specific vaccine when developed. Immediate vaccination with a non-clade matched vaccine, even with reduced efficacy, would prevent thousands of new infections in SF and millions in SA over 30 years. Vaccination with 50% VE delayed for five years needs six and 12 years in SA to break-even with immediate 20 and 30% VE vaccination, respectively, while not able to surpass the impact of immediate 40% VE vaccination over 30 years. Replacing a 30% VE with a 50% VE vaccine after 5 years reduces the HIV acquisition by 5% compared to delayed vaccination. The immediate use of an HIV vaccine with reduced VE in high risk communities appears desirable over a short time line but higher VE should be the pursued to achieve strong long-term impact. Our analysis illustrates the importance of developing surrogate markers (correlates of protection) to allow bridging types of immunogenicity studies to support more rapid assessment of clade specific vaccines.

Keywords: ART, antiretroviral therapy; HIV epidemic; HIV prevention; HIV, human immunodeficiency virus; Intervention effectiveness; Mathematical modeling; NHP, non-human primates; SA, South Africa; SF, San Francisco; VE, vaccine efficacy; Vaccine efficacy.

Fig. 1

Flow diagram of the model of HIV transmission under the replacement vaccination strategy. Simulated population is stratified in compartments by HIV and vaccination status as susceptibles (S), susceptibles vaccinated with non-matched (V) or clade-specific vaccines (Vⁿ), HIV-positive who become infected when unvaccinated (I) or vaccinated (I^v), and individuals with AIDS (A). Non-matched vaccine (red flows) is used initially and replaced with clade-specific vaccine (blue flows) when it becomes available in all new vaccinations (vaccination rate ν) and revaccinations (revaccination rate γ).

Fig. 2

Projected number of HIV infections over 10, 20 and 30 years in a) South Africa and b) San Francisco. Epidemic projections without vaccine (blue) are compared to scenarios in which 50% effective vaccine is available immediately (red) and vaccination coverage projected in Fig. S1. Bars (whiskers) represent mean (90% uncertainty interval) of the projections generated by 1000 epidemic simulations representative of each epidemic setting. All scenarios assume no changes in sexual behavior due to vaccine use.

Fig. 3

Effectiveness of different vaccine interventions in South Africa (left) and San Francisco (right) measured by a–b) cumulative fraction of HIV infections prevented; c–d) reduction in HIV prevalence and e–f) reduction in HIV incidence over a period of 30 years. Epidemic projections without vaccine (solid black lines) are compared to scenarios in which 20–40% effective non-specific vaccine is available immediately (dashed and dotted black lines) and scenarios in which 50% effective clade-specific vaccine becomes available after a development delay of 3 to 8 years (colored lines). All lines represent median projections generated by 1000 epidemic settings representative of each epidemic setting. All scenarios assume no changes in sexual behavior due to vaccine use.

Fig. 4

Time needed (break even time) for a 50% effective clade-specific vaccine introduced in South Africa (left) and San Francisco (right) after a development delay of 1 to 10 years to surpass a 20–40% effective non-matched vaccine introduced immediately in a–b) number of new infections prevented and c–d) reduction in HIV prevalence. Mean projections generated by 1000 epidemic settings representative of the HIV epidemic in South Africa and San Francisco. Break-even times are consistent across simulated epidemics with all projections being within 1-year difference from the mean (not shown). All scenarios assume no changes in sexual behavior due to vaccine use.

Fig. 5

Comparison of immediate, delayed and replacement vaccination strategies. Projected effectiveness in terms of proportion of new infections prevented over 10, 20 and 30 years in a) South Africa and b) San Francisco. The bars represent the median projections generated by 1000 epidemic settings representative of the HIV epidemic in South Africa and San Francisco. All scenarios assume no changes in sexual behavior due to vaccine use.