New Prospects for a Preventive HIV-1 Vaccine

The immune correlates of risk analysis and recent non-human primate (NHP) challenge studies have generated hypotheses that suggest HIV-1 envelope may be essential and, perhaps, sufficient to induce protective antibody responses against HIV-1 acquisition at the mucosal entry. New prime-boost mosaic and conserved-sequence, together with replicating vector immunisation strategies aiming at inducing immune responses or greater breadth, as well as the development of immunogens inducing broadly neutralising antibodies and mucosal responses, should be actively pursued and tested in humans. Whether the immune correlates of risk identified in RV144 can be extended to other vaccines, other populations, or different modes and intensity of transmission, and against increasing HIV-1 genetic diversity, remains to be demonstrated. Although NHP challenge studies may guide vaccine development, human efficacy trials remain key for answering the critical questions leading to the development of a global HIV-1 vaccine for licensure.

Table 1

Completed human HIV-1 vaccine efficacy trials

Trial	Details	Population	Area	Outcome
Vax004	AIDSVAX B/B gp120 (MN and GNE8 subtype B) gp120 in alum	MSM* and women who engage in high-risk behaviour	USA and Europe	No efficacy
Vax003	AIDSVAX B/E gp120 (subtype B MN and CRF01_AE CM244) gp120 in alum	PWID†	Thailand	No efficacy
HVTN 502/Merck 023/Step trial	MRKAd5‡ HIV-1 Gag/Pol/Nef subtype B	High-risk population, MSM, heterosexual men and women	USA	No efficacy
HVTN 503/ Phambili trial	MRKAd5 HIV-1 Gag/Pol/Nef subtype B	Heterosexual men and women	Republic of South Africa	No efficacy; increased HIV infection observed in vaccinees
RV144	ALVAC-HIV§ (vCP1521) and AIDSVAX B/E (subtype B MN and CRF01_AE CM244) rgp120 in alum	Community risk	Thailand	31.2% efficacy against HIV acquisition at 42 months, 60% at 12 months. No effect on plasma viral load and CD4 count
HVTN 505	DNA Gag, Pol, and Nef from HIV-1 subtype B and Env from subtypes A, B, and C and rAd5 subtype B Gag-Pol and Env A, B, and C	Circumcised MSM and transgender individuals lacking infection with Ad5	USA	No efficacy

*Men who have sex with men;

†people who inject drugs;

‡MRKAd5: recombinant replication-incompetent Ad5 vector;

§ALVAC-HIV: recombinant canarypox vector

Table 2

Immune correlates of risk identified in HIV-1 vaccine efficacy trials

Trial	Details
RV144	Plasma IgG binding antibody to gp70V1V2 scaffold proteins (subtypes B, A, C and CRF01_AE) inversely correlated with risk of infection
	Plasma IgA-envelope binding antibodies correlated with risk
	In vaccine recipients with low plasma IgA antibodies, an inverse correlation was observed between rate of infection and Env-specific CD4+ T cells, ADCC, neutralising antibodies, and Env IgG avidity
	Sieve analysis showed two positions in V2 (169 and 181), which substantiates the hypothesis that protection resulted from vaccine-induced responses against V2 loop
	Positive association between the FcγRIIC polymorphism and vaccine efficacy
	Env IgG3 correlated with decreased risk of HIV infection
Vax004	ADCVI inverse correlated with rate of HIV acquisition
	High levels of neutralising antibodies to MN inversely correlated with HIV incidence
	Fcγ receptor IIIa genotype was associated with an increased rate of HIV-1 infection in low-risk, but not in high-risk vaccinees
Vax003	No correlates identified
Step trial (HVTN 502)	Presence of HLA alleles and overall T-cell breadth and magnitude of the immune response significantly correlated with lower mean viral load in infected vaccinees suggesting the implication of CD8+ cytotoxic T lymphocytes
	Non-HIV-specific ELISPOT magnitude was a significant direct CoR for HIV-1 infection in vaccinees
Vax003	Analysis ongoing

CoR: correlate of risk

Full article at: http://goo.gl/QvOOUP

By: Jeffrey Brown,1 Jean-Louis Excler,*,1,2 and Jerome H Kim3

¹US Military HIV Research Program, Bethesda, MD, USA

²The Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA

³US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA

^*Corresponding author: Jean-Louis Excler, US Military HIV Research Program, 6720-A Rockledge Drive, Suite 400 Bethesda, MD 20817, USA ;Email: gro.hcraeservih@relcxej

All authors equally contributed to the preparation of this manuscript.

  

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