Novel directions in HIV-1 vaccines revealed from clinical trials

Abstract

Purpose of review

Considerable HIV-1 vaccine development efforts have been deployed over the past decade. Put into perspective, the results from efficacy trials and the identification of correlates of risk have opened large and unforeseen avenues for vaccine development.

Recent findings

The Thai efficacy trial, RV144, provided the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop inversely correlated with decreased risk of infection, while Env-specific IgA directly correlated with risk. Further clinical trials will focus on testing new envelope subunit proteins formulated with adjuvants capable of inducing higher and more durable functional antibody responses (both binding and broadly neutralizing antibodies). Moreover, vector-based vaccine regimens that can induce cell-mediated immune responses in addition to humoral responses remain a priority.

Summary

Future efficacy trials will focus on prevention of HIV-1 transmission in heterosexual population in Africa and men who have sex with men in Asia. The recent successes leading to novel directions in HIV-1 vaccine development are a result of collaboration and commitment among vaccine manufacturers, funders, scientists and civil society stakeholders. Sustained and broad collaborative efforts are required to advance new vaccine strategies for higher levels of efficacy.

Introduction

Globally, 34.0 million people were living with HIV-1 at the end of 2011. Sub-Saharan Africa remains most severely affected, accounting for 69% of the people living with HIV-1 worldwide. The number of newly infected people and the AIDS-related mortality continue to fall [1]. Despite this incremental and fragile success, the development of a cost-effective preventive HIV-1 vaccine remains among the best hopes for controlling the HIV-1/AIDS pandemic [2,3]. In 2009, vaccine efficacy against HIV-1 acquisition was demonstrated in humans for the first time. This breakthrough finding has opened unprecedented avenues to accelerating the development of a vaccine suitable for licensure. Our paper reviews the main advances and challenges.

Lessons learnt from clinical trials

Experimental preventive HIV-1 vaccines have been administered to over 44,000 human volunteers in over 187 separate trials since 1987, tested mostly in Phase I/II clinical trials. The different HIV-1 vaccine approaches along with their scientific and programmatic challenges have been reviewed elsewhere [2,4–9]. Table 1 lists the combinations, route and mode of administration of vaccine concepts tested more recently in Phase I/II trials, while Table 2 summarizes their main immunogenicity findings.

Table 1.

Generic HIV-1 vaccine candidates including mode and route of administration, recently tested in Phase I/II trials

Vaccine Products	HIV-1 Subtype	Adjuvant, Formulation	Mode and Route of Administration	References
Subunits
Lipopeptides	B		IM	[10,11]
Oligomeric gp160	B	DC-Chol	Nasal, Vaginal	ANRS VAC14
Trimeric gp140	B’/C	Carbopol, GLA, Chitosan	Vaginal, IM, IN, Oral	[12]
Trimeric gp140	B, C	PCPP, MF59	IM	[13]
Tat protein	C	Alum	SC, ID	[14,15]
Fusion protein Env-Nef-Tat	B	AS02A, AS02V, AS01B	IM	[16,17]
gp41 P1 peptide		Virosomes	IM, IN	[18]
Pox vectors
ALVAC (vCP1521)	CRF01_AE		IM	[19]
Replicating vaccinia (VV Tiantan)	B’/C		Scarification	[20]
Modified Vaccinia Ankara (MVA)	A, B, C		IM	[21–23]
NYVAC	C		IM	[24]
DNA
	A, B, C		IM, EP	[25–28]
Conserved epitopes	Multiclades		IM	[29–31]
PENNVAX	B	IL-12, IL-15	IM, EP	[32]
Replication-defective Adenovirus Vectors
Ad5	B		IM	[33,34]
Ad35	B, A		IM	[35]
Ad26	A		IM	[36,37]
Adeno-associated Virus Vector type 2	C		IM	[38–40]
Alphavirus Replicon VEE	C		IM	[41]
Replication-competent Measles Vector	B		IM	Ongoing
Vesicular Stomatitis Virus Vector	B		IM	Ongoing, [42]
Prime-Boost Combinations
DNA + Trimeric V2-deleted gp140	B	PLG, MF59	IM	[43]
DNA + Env subunit	A, B, C, CRF01-AE	QS-21	ID, IM	[44,45]
DNA + MVA	A, B, C, CRF01_AE, B epitopes	GMCSF	IM, ID, Biojector*	[46–56]
DNA + Fowlpox	B		IM	[57,58]
DNA + VV Tiantan	B’/C		Scarification	[20]
DNA + NYVAC	C		IM	[59–61]
Ad5 + NYVAC	A, B, C and B		IM	[62]
DNA + Ad5 or Ad35	A, B, C		Biojector*, IM, ID, SC	[63–68]
DNA IL-12 EP + Ad35-GRIN/ENV	B, A		EP, IM	Ongoing, [69]
DNA + MVA + ChAdV63	Conserved sequences		IM	Ongoing, [70]
DNA + VSV	B	IL-12	EP, IM	Ongoing
MVA + Fowlpox	B		IM	[71,72]
Ad35 env + Ad26 env	A		IM	Ongoing
ALVAC (vCP1521) + AIDSVAX B/E gp120	B, CRF01_AE	Alum	IM	Ongoing
Ad26 env A + MVA (natural vs. mosaic)	A, CRF01_AE, mosaic		IM	Ongoing
Ad35-GRIN + adjuvanted fusion protein (non-Env)	A, B		IM	Ongoing
Ad35-GRIN + replicating Sendai	A		IM, IN (Sendai)	Ongoing

Pox: Recombinant Poxvirus-vectored vaccine; ALVAC: recombinant canarypox vector

Ad5: Replication-defective recombinant Adenovirus subtype 5; ChAdV63: Replication-defective recombinant Chimpanzee adenovirus subtype 63

MVA: Modified Vaccinia Ankara; VEE: Venezuelan equine encephalitis; VV Tiantan: Attenuated replicating vaccinia Tiantan developed in China

EP: Electroporation; GLA: Glucopyranosyl Lipid Adjuvant

GRIN: gag, reverse transcriptase, integrase, and nef genes from HIV-1 subtype A

GRIN/ENV: Ad35-GRIN + Ad35 expressing env gp140 from HIV-1 subtype A

PCPP: Polyphosphazene; IFA: Incomplete Freund’s Adjuvant

Sendai: replication-competent murine parainfluenza type 1 paramyxovirus

^*For DNA only

Table 2.

Main immunogenicity findings of Phase I/II trials

No broadly neutralizing antibodies are induced by current vaccines.

Binding antibodies and neutralizing antibodies against Tier-1 and limited Tier-2 HIV-1 isolates were induced by Env subunit proteins formulated with potent adjuvants.

Polyfunctional CD4+ and CD8+ T-cell responses measured by ICS and INF-γ ELISpot assays generally of low to moderate magnitude immune responses have been detected in a majority of vaccinees immunized by vectors alone and to some extent by DNA alone. These responses are generally significantly augmented after priming.

CD8-mediated inhibition of in vitro viral replication can be detected after vector-based vaccination.

Cell-mediated responses to DNA administered by electroporation are significantly augmented compared to intramuscular needle injection

Systems biology can identify specific gene activation immune signatures predictive of the immune responses

Pre-existing immunity to pox vectors does not or minimally impact on the pox vector vaccine-induced immune responses, in particular after DNA prime

Pre-existing immunity to Ad5 (high prevalence) decreases the Ad5 vaccine-induced immune responses, which led to the development of low prevalence rare serotype adenovirus vectors.

Env subunit protein boosts induce higher levels of serum antibodies that rapidly wane.

A key goal for an effective HIV-1 vaccine is to induce responses that differ qualitatively, quantitatively, or both from that induced by natural infection [73]. Phase I/II trials provides fundamental information about safety and immunogenicity, but not about the relevance of those immune responses to protective efficacy. In the absence of a link to sufficient efficacy endpoints, flurries of new vaccine concepts have aimed at inducing immune responses of uncertain relevance.

Modern assessments have revealed that the majority of successfully licensed vaccines protect through elicitation of protective antibodies [74–77]. It has been postulated that with our limited current knowledge on correlates of protection, induction of both humoral and cell-mediated immune responses are important to combat HIV-1 in the peripheral compartment and in the mucosal tissues, the entry point of the virus [78]. These considerations led to develop vaccine strategies such as the concept of ‘prime-boost’ vaccination aiming at inducing and augmenting both types of responses [79–81]. Innate immune activation has also been a desired addition and new systems biology tools have become available to provide a framework to compare immune signatures that might predict subsequent HIV-1-specific immune responses induced by vaccines [82,83*].

Safety

The vast majority of candidate vaccines were generally safe and well tolerated, including those delivered using new modes (Biojector and electroporation) and routes (intravaginal, nasal, oral) of administration. While there have been regional differences, background morbidity of healthy participants at low risk for HIV-1 infection selected for Phase I/II trials has not posed an obstacle to clinical trial conduct and interpretation [84]. The RV144 prime-boost regimen tested for efficacy (ALVAC-HIV, vCP1521 and gp120 in alum, AIDSVAX B/E) exhibited a remarkable safety profile in more than 8000 Thai vaccinees [19]. ALVAC-HIV (vCP1521) was also been found to be safe in infants born to HIV-1-infected mothers [85].

Following the Step trial (HVTN 502) outcome in 2007, in which Ad5 vector-based vaccinees were at higher risk of HIV acquisition than placebo recipients, concerns were raised about the use of new vectors, in particular adenovirus-based vectors. In subjects with pre-existing Ad5-specific neutralizing antibody (NAb) titers, a greater number of HIV-1 infections occurred in vaccinees. Post-hoc multivariate analysis suggested that the greatest increased risk was in men who had pre-existing Ad5-NAb and were uncircumcised [86]. The vaccine-associated risk waned with time from vaccination [87]. The increased HIV-1 infection rate observed among uncircumcised men was not supported by a behavioral explanation [88]. The presence of Ad5-NAb was not linked to the risk of HIV-1 acquisition among unvaccinated populations at elevated risk of HIV-1 infection [89]. Anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-infected compared to uninfected controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups [90]. Given the unclear significance of these findings, close monitoring of such events is warranted in future efficacy trials with recombinant adenovirus vectors.

Increasing interest in potent adjuvants administered systemically or mucosally to bolster immune responses, has introduced other safety concerns. Following administration of a polyvalent DNA prime-protein boost HIV-1 vaccine formulated with QS21, two subjects developed strong delayed-type hypersensitivity reactions with cutaneous leukocytoclastic vasculitis and Henoch-Schonlein purpura [91]. Although such events are rare, safety and tolerability needs to be carefully monitored following the administration of adjuvanted proteins in prime-boost regimens.

Another concern, unrelated to safety, is the potential social harm that comes from vaccine-induced seropositivity (VISP) in uninfected vaccinees. The use of vaccines expressing several HIV-1 proteins, as well as HIV-1 envelope subunit proteins formulated with adjuvants, has led to an increasing proportion of vaccinated individuals testing HIV-1 positive with routine diagnostic tests. This has raised growing concern in communities targeted for HIV-1 vaccination and with health authorities regarding the differentiation of VISP from true HIV-1 infection [92]. For example, more than 80% of volunteers vaccinated with an adjuvanted envelope subunit protein still tested HIV-1 positive 8 years post vaccination [93]. Although Western Blot and nucleic acid tests may allow this differentiation, the development of cheaper and easier-to-run antibody-based diagnostic tests able to differentiate VISP from HIV-1 infection is actively pursued [94–96].

Correlates of risk: Lessons from Phase IIB and III Trials

Table 3 summarizes the completed and ongoing clinical efficacy trials. The detailed analysis of vaccine-elicited immune responses, virus sieve analysis of breakthrough infections and host genetics have all provided invaluable information into potentially protective immune responses, regardless of outcome. Each of these trials underpins the current rationale for planned HIV-1 vaccine trials.

Table 3.

Completed and ongoing Phase IIb and III human HIV-1 vaccine trials

Study Protocol	Candidate Vaccine	Phase	Sample Size	Population enrolled	Location	Result	References
HVTN 505	DNA (VRC-HIVDNA016-00-VP) and rAd5 (VRC-HIVADV014-00-VP) (A, B, and C)	IIb	2,494 in MITT analysis	Circumcised MSM and TG Ad5 Ab negative	USA	Stopped for futility. No efficacy on HIV acquisition and on plasma viral load	www.niaid.nih.gov/news/QA/Pages/HVTN505qa2013.aspx
RV144	ALVAC-HIV vCP1521 and AIDSVAX B/E (MN and CRF01_AE CM244) rgp120 in alum	III	16,403	Community	Thailand	31.2% efficacy against HIV-1 acquisition. No effect on plasma viral load	[19,97**,98,99*,100**,101–103**,104,105*,106,107]
HVTN 502 Step trial	MRKAd5 HIV-1 gag/pol/nef B	IIb	3,000	MSM, high-risk heterosexual men and women	North and South America, Australia, Caribbean	No efficacy; transiently increased infection risk Stopped	[87,108**–115]
HVTN 503 Phambili trial	MRKAd5 HIV-1 gag/pol/nef B	IIb	3,000 801 enrolled	Heterosexual men and women	South Africa	No efficacy – Stopped Follow-up analysis suggests increase rate of HIV infection in vaccine recipients	[116,117]
Vax003	AIDSVAX B/E gp120 (MN and CRF01_AE CM244) gp120 in alum	III	2,500	Injecting Drug Users	Thailand	No efficacy	[118]
Vax004	AIDSVAX B/B gp120 (MN and GNE8) gp120 in alum	III	5,400	MSM, high risk women	USA	No efficacy	[119–125]

MITT: modified intent-to-treat analysis

ALVAC-HIV (vCP1521): recombinant canarypox vector expressing Gag and Protease subtype B (LAI) and env gp120 CRF01_AE (TH023) linked to the transmembrane-anchoring portion of subtype B gp41 (LAI) genes.

Ad5: Replication-defective recombinant Adenovirus 5-vectored vaccine; Ad5 Ab: Ad5-specific neutralizing antibody

VRC-HIVDNA-016-00-VP: DNA plasmids expressing Gag, Pol, and Nef subtype B (strains HXB2, NL4-3, NY5/BRU, respectively) and HIV-1-1 Env subtype A (strain 92rw020), B (strains HXB2/BaL), and C (strain 97ZA012)

VRC-HIVADV014-00-VP: mixture of four rAd5 vectors encoding the HIV-1 Gag-Pol polyprotein subtype B (strains HXB2-NL4-3) and Env A, B and C matching the DNA Env components

MSM: men who have sex with men; TG: male-to-female transgender persons who have sex with men

The Vax003 and Vax004 trials evaluated the efficacy of recombinant HIV-1 gp120 proteins. They have provided important insights into vaccine-elicited immune responses and the potential bar that needs to be overcome for further HIV-1 vaccine efficacy studies. In Vax004, higher NAb responses to an easy-to-neutralize virus (MN) corresponded with lower risk of infection in the vaccine group. Evidence of low-level NAb responses against more-difficult-to-neutralize viruses suggests that level and breadth were not sufficient for protection [119]. However, other studies reported that antibody-dependent cellular virus inhibition (ADCVI) corresponded with a decreased HIV-1 infection rate [120] suggesting that beneficial immune responses did not reach sufficient magnitude to impact the outcome of the trial. Host genetics may have also played a role in the vaccinee outcome. While there was no evidence of increased HIV acquisition in vaccinees relative to placebo recipients, there has been suggestion that the vaccine may have increased the likelihood of acquiring HIV-1 infection in low-behavioral risk individuals with the Fcγ receptor IIIa genotype [121].

RV144 is the only HIV-1 vaccine efficacy trial to date that has demonstrated vaccine efficacy, with a modest level of protection of 31% [97]. Humoral responses were the predominant immune response in this trial, along with vaccine-elicited CD4+ T-cell responses [98,99]. A case-control study showed that IgG antibodies to the V1/V2 region of HIV-1 gp120 correlated with decreased risk of infection [100–102] while IgA antibodies to the envelope correlated with decreased vaccine efficacy in the vaccine group.

Follow-up studies further supported the role of V2-specific immunity in vaccine efficacy with evidence of a virus sieve effect in infected vaccine recipients at this gp120 region [103]. Additionally, monoclonal antibodies generated from RV144 vaccine recipients targeted a critical residue in V2 (K169), thus providing evidence that vaccine-induced antibodies could potentially mediate a virus sieve effect. These V2-specific antibodies can mediate ADCC, neutralization and low-level virus capture [126,127]. These studies do not prove whether the V2 IgG response was a mechanistic or non-mechanistic correlate [128*]. They however generate new hypotheses to test in further efficacy clinical trials; namely, is there a functional role for V2-specific IgG antibodies or are they merely a marker of another functional immune response?

The plasma IgA antibody combined with the lack of knowledge of whether mucosal immune responses were elicited by vaccination has led to renewed interest in understanding the different forms of IgA and their potentially protective functions. Several RV144 follow-up studies as well as new vaccine studies are now collecting mucosal samples to probe these questions and determine the functional properties of vaccine-elicited IgA responses. In RV144, in the presence of low vaccine-elicited IgA responses, either ADCC or NAb responses correlated with decreased risk of infection. ADCC responses were predominantly directed to the C1 conformational region of gp120 [129–131] although other epitope specificities (i.e., V2) also contributed to the overall response [126]. Another hypothesis is that C1 region Env-specific IgA could block C1-specific IgG effector function due to their ability to bind to different Fc receptors on effector cells. We recently demonstrated that IgA antibodies elicited by RV144 could block C1 region-specific IgG-mediated ADCC (via natural killer cells) [132]. These findings indicate that the study of Fc receptor-mediated antibody function will be important in the evaluation of HIV-1 vaccines. In addition, there is a remaining open question as to whether V2 antibodies might block the gp120-α4β7 interaction and contribute at least partially to the protective effect against HIV-1 sexual transmission [133].

Despite the 31% protective efficacy observed in RV144 and the lack of protection in Vax003, NAb responses were lower in RV144 as compared to Vax003 [99*]. The interpretation of these findings between the two trials remains difficult, as the route of HIV-1 transmission (heterosexual vs. IDU) was radically different. In previous clinical studies, it was found that gp120 induced high levels of Env-specific IgG4 antibodies [134] while ALVAC (vCP1452) prime and gp120 MN in alum boost elicited lower IgG4 relative to IgG1 and IgG3 antibodies [134]. Antigen-specific IgG3 antibodies have been associated with control of the pathogen and clinical protection in several infectious diseases [136,137]. A comparative study of IgG subclasses between RV144 and Vax003 may provide additional clues to mechanisms of vaccine protection.

The Step (HVTN502) [108] and Phambili (HVTN503) [116] studies were the first human efficacy trials of a T-cell-based HIV-1 vaccine. Despite an absence of vaccine efficacy, there was evidence of vaccine-elicited immune pressure on the founder virus [109]. This virus sieve analysis suggests that there were vaccine-elicited T-cell responses potentially not picked up by the IFN-γ ELISpot assays and that vaccine elicited Gag- and Nef-specific CD8+ T cells [110] applied pressure to the virus resulting in specific escape mutations in those with specific HLA alleles. Moreover vaccinees with HLA alleles associated with HIV-1 control had a significantly lower mean viral load over time [138]. Interestingly, the most highly conserved epitopes were detected at a lower frequency, suggesting that stronger responses to conserved sequences may be as important as breadth for protection [139]. Very recently, HVTN 505 was stopped for futility, showing no efficacy and no statistically significant effect on viral load as well as a non-significant increase in the number of HIV infections among vaccine recipients compared to the placebo group (Table 3). Similarly, a recent follow-up analysis of HVTN503 participants suggests a non-significant increased rate of HIV infection in the vaccinees compared to placebo recipients [117]. Further analysis is needed to better understand the immunogenicity of the HVTN505 and HVTN503 vaccines and how these results might inform the development of other adenoviruses vectors.

New directions

Table 4 shows some of the clinical trials planned within the next 5 years based on lessons learned from recent trials.

Table 4.

Planned and foreseen clinical trials within the next 5 years

Vaccine regimens	Phase	Country	Concepts tested based on lessons learned
RV305: ALVAC-HIV (vCP1521) + AIDSVAX B/E	I	Thailand	Comparison of late boosts in RV144 vaccinees; memory of antibody response (V2); immune responses in peripheral and mucosal compartments
RV306: ALVAC-HIV (vCP1521) + AIDSVAX B/E	I	Thailand	RV144 regimen + one-year boost: augment and sustain Env antibody response, in particular V2, ADCC, IgG subclasses, IgA in peripheral and mucosal compartments; CMI in gut tissues; innate immunity
RV328: AIDSVAX B/E	I	Thailand	Env antibodies and CMI responses in peripheral and mucosal compartments
RV307: Ad26 env A + MVA natural vs. mosaic	I	Thailand, Kenya, Uganda	Heterologous vector prime-boost; breadth, depth and memory of CMI responses induced by mosaic vs. natural genes; Env antibodies
Ad26 mosaic + MVA mosaic ± adjuvanted Env subunit protein	I–IIB	Thailand, Kenya, Uganda, Mozambique	Heterologous vector prime-boost; breadth, depth and memory of CMI responses induced by mosaic genes; induction of Env antibodies
ALVAC + adjuvanted Env subunit protein	I–III	Thailand, RSA	Improved Env design to induce V2 antibodies; Efficacy and mode of transmission: heterosexual population at high risk in RSA and in MSM
DNA + NYVAC ± adjuvanted Env subunit protein	I–IIB	RSA, Southern Africa	DNA + pox vector for potent CMI responses; Env boost for antibodies; Efficacy in heterosexual population at high risk; adaptive trial designs
DNA + Vaccinia ± adjuvanted Env subunit protein	IIB	China	DNA + pox vector for potent CMI responses; Env boost for antibodies; Efficacy in MSM
New trimeric Env subunit proteins and adjuvants	I	US, UK, Africa	Induction of broadly neutralizing antibodies in peripheral and mucosal compartments; systemic and mucosal administration
Vaccine and PrEP or microbicides	I–IIB	To be determined	Synergistic effect of prevention technologies

CMI: cell-mediated immunity; MSM: men who have sex with men; ADCC: antibody-dependent cell-mediated cytotoxicity; RSA: Republic of South Africa

One of the main objectives for future vaccines is to counter HIV-1 variability. Several groups are focused on designing novel envelope immunogens capable of inducing broadly NAb [140–143]. This work is being based on study of envelope structure and host-pathogen interactions aimed at guiding the immune response toward the vulnerable sites on the envelope. Improvement of existing envelope immunogens to elicit higher levels of V2 antibodies is an approach suggested by antigenicity studies of the envelope used in RV144. These studies demonstrated that certain epitopes were better exposed as a result of a non-HIV-1 sequence inserted into the HIV-1 envelope and likely led to the elicitation of antibody epitope specificities in RV144 [144]. Whether V2 antibodies elicited by various envelope immunogens are functional in a cross-clade manner and universal correlates of risk or just the ‘tree hiding the forest’ remains to be demonstrated. Vaccines utilizing a combination of consensus and transmitter-founder envelopes may be able to induce neutralizing responses with greater breadth and potency than single envelope immunogens [145]. Whether the induction of IgA blocking ADCC is a potential ‘spine on the rose’, and how to overcome it, also remains to be explored.

Mucosal IgA responses are elicited in acute HIV-1 infection but are focused predominantly on gp41 (and not gp120) and decline rapidly after the acute phase [146]. Several studies in non-human primates have reported the elicitation of mucosal immunity by different vaccine regimens [reviewed in 147]. Interestingly, a gp41-derived peptide formulated on virosomes protected macaques against SHIV challenge and elicited mucosal IgA and IgG antibodies in the protected animals [148]. The same vaccine administered in humans via systemic and mucosal routes elicited limited IgG and IgA antibodies in mucosal secretions [18]. Further clinical trials with mucosal sampling will provide additional insights in the ability of different vaccine regimens to elicit mucosal antibodies. Moreover, some emerging vaccine strategies aim at inducing long-lived memory B-cell responses.

Combination regimens using heterologous vectors in prime-boost and inserts aiming at broadening CD4+ and CD8+ T-cell responses such as mosaics [149] and conserved sequences [150] are promising avenues. Alternative vectors that might minimize or eliminate the presence of pre-existing anti-vector immunity [151] such as rare serotype human [152] and chimpanzee [153,154] adenovirus vectors as well as replication-competent vectors [155] are now in early clinical development (Table 4). It remains however uncertain how the recent outcomes of HVTN505 and HVTN503 may impact the use of adenovirus vectors in humans.

Unmet needs and opportunities

Significant efforts are currently focused on advancing efficacy trials in sub-saharan African with an emphasis on South Africa, due to the ongoing devastating subtype C HIV-1 epidemic. The HIV-1 subtype A epidemic also remains rampant in East Africa [156–158], which will demand similar efforts in the future. While heterosexual transmission predominates in sub-saharan Africa [159], an epidemic in men who have sex with men (MSM) is now expanding [160,161]. MSM will represent the predominant high-risk population for future HIV-1 vaccine efficacy trials in Asia [162–164]. The feasibility of efficacy testing in IDU is questionable due to the success of harm reduction programs [165] with decreasing HIV-1 incidence. The identification of low–intermediate-risk populations with predominant heterosexual transmission in Asia should however deserve heightened attention for the implementation of future efficacy trials [166].

Adaptive trial designs that would allow for the ongoing comparative evaluation of multiple vaccine concepts have been suggested as way to inform immune correlates analysis and enhance the efficiency of efficacy evaluation of HIV-1 vaccine candidates [167]. They may also help address the complexities of evaluating the efficacy of multiple HIV prevention measures in combination [168,169].

Conclusion

Preventive HIV-1 vaccine clinical development is at a critical juncture due to the identification of correlates of HIV-1 infection risk from RV144. These findings have opened new avenues of research that were previously unforeseen and only made possible through the conduct of large-scale efficacy trials, in-depth analysis of immune response with modern laboratory assays, detailed statistical analysis and modeling, interdisciplinary teams, and strong international collaborations.

Key Points.

• Vaccine-induced protection against HIV acquisition has been demonstrated

• Correlates of risk for HIV acquisition have been identified

• Immunogens inducing broadly neutralizing antibodies are being designed

• Heterosexual populations in Africa and men who have sex with men in Asia are potential target for future efficacy trials

• Strong international collaborations along with sustained political and funding commitments are necessary to develop and bring to licensure a safe and efficacious HIV vaccine