Current Opinion in HIV & AIDS:
CHANGING ENVIRONMENT IN HIV VACCINE: Edited by Nelson L. Michael and Glenda Gray
Novel directions in HIV-1 vaccines revealed from clinical trials
Excler, Jean-Louisa; Tomaras, Georgia D.b,c,d; Russell, Nina D.e
aU.S. Military HIV Research Program (MHRP), Bethesda, Maryland
bDuke Human Vaccine Institute, Department of Surgery
cDuke Human Vaccine Institute, Department of Immunology
dDuke Human Vaccine Institute, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina
eBill & Melinda Gates Foundation, Seattle, Washington, USA
Correspondence to Jean-Louis Excler, MD, U.S. Military HIV Research Program (MHRP), 6720-A Rockledge Drive, Suite 400, Bethesda, MD 20817, USA. Tel: +63 947 893 7459; e-mail: firstname.lastname@example.org
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 a decreased risk of infection, whereas 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 MSM 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.
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 . 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 article 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 [2,4–6,7▪,8,9]. Table 1 lists the combinations, route and mode of administration of vaccine concepts tested more recently in phase I/II trials [10–72]. Main immunogenicity findings of Phase I/II trials are listed as follows:
Table 1-a Generic HI...Image Tools
1. No broadly neutralizing antibodies are induced by current vaccines.
2. 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.
3. Polyfunctional CD4+ and CD8+ T-cell responses measured by ICS and IFN-γ ELISpot assays generally of low to moderate magnitude immune responses have been detected in a majority of vaccines immunized by vectors alone and to some extent by DNA alone. These responses are generally significantly augmented after priming.
4. CD8-mediated inhibition of in-vitro viral replication can be detected after vector-based vaccination.
5. Cell-mediated responses to DNA administered by electroporation are significantly augmented compared with intramuscular needle injection.
6. Systems biology can identify specific gene activation immune signatures predictive of the immune responses.
7. Pre-existing immunity to pox vectors does not or minimally impact on the pox vector vaccine induced immune responses, in particular after DNA prime.
8. 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.
9. 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 . Phase I/II trials provide 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 is important to combat HIV-1 in the peripheral compartment and in the mucosal tissues, the entry point of the virus . 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▪].
The vast majority of candidate vaccines were generally well tolerated, including those delivered using new modes (Biojector and electroporation) and routes (intravaginal, nasal, oral) of administration. Although there have been regional differences, background morbidity of healthy participants at a low risk for HIV-1 infection selected for phase I/II trials has not posed an obstacle to clinical trial conduct and interpretation . 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 . ALVAC-HIV (vCP1521) was also been found to be well tolerated in infants born to HIV-1-infected mothers .
Following the Step trial (HVTN 502) outcome in 2007, in which Ad5 vector-based vaccinees were at a higher risk of HIV acquisition than placebo recipients, concerns were raised about the use of new vectors, in particular adenovirus-based vectors. In individuals with pre-existing Ad5-specific neutralizing antibody (NAb) titres, a greater number of HIV-1 infections occurred in vaccinees. Posthoc multivariate analysis suggested that the greatest increased risk was in men who had pre-existing Ad5-NAb and were uncircumcised . The vaccine-associated risk waned with time from vaccination . The increased HIV-1 infection rate observed among uncircumcised men was not supported by a behavioural explanation . The presence of Ad5-NAb was not linked to the risk of HIV-1 acquisition among unvaccinated populations at an elevated risk of HIV-1 infection . Antivector immunity differed qualitatively in Ad5 seropositive participants who became HIV-infected compared with uninfected controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected individuals compared with uninfected controls, whereas seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups . Given the unclear significance of these findings, close monitoring of such events is warranted in future efficacy trials with recombinant adenovirus vectors.
An 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 individuals developed strong delayed-type hypersensitivity reactions with cutaneous leukocytoclastic vasculitis and Henoch-Schonlein purpura . 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 . For example, more than 80% of volunteers vaccinated with an adjuvanted envelope subunit protein still tested HIV-1 positive 8 years postvaccination . 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 [93–95].
Correlates of risk: lessons from phase IIB and III trials
Table 2 summarizes the completed and ongoing clinical efficacy trials [19,86–90,96▪▪,97,98▪,99▪▪,100,101,102▪▪,103,104▪,105,106,107▪▪,108–120]. 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.
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 a 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 . However, other studies reported that antibody-dependent cellular virus inhibition (ADCVI) corresponded with a decreased HIV-1 infection rate , 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 vaccine outcome. Although 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-behavioural risk individuals with the Fcγ receptor IIIa genotype .
RV144 is the only HIV-1 vaccine efficacy trial to date that has demonstrated vaccine efficacy, with a modest level of protection of 31% [96▪▪]. Humoral responses were the predominant immune response in this trial, along with vaccine-elicited CD4+ T-cell responses [97,98▪]. A case–control study showed that IgG antibodies to the V1/V2 region of HIV-1 gp120 correlated with a decreased risk of infection [99▪▪,100,101], whereas IgA antibodies to the envelope correlated with a 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 [102▪▪]. In addition, mAbs 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 antibody-dependent cellular cytotoxicity (ADCC), neutralization and low-level virus capture [121,122]. These studies do not prove whether the V2 IgG response was a mechanistic or nonmechanistic correlate [123▪]. 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 a decreased risk of infection. ADCC responses were predominantly directed to the C1 conformational region of gp120 [124–126], although other epitope specificities (i.e. V2) also contributed to the overall response . 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. It was recently demonstrated that IgA antibodies elicited by RV144 could block C1 region specific IgG-mediated ADCC (via natural killer cells) . 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 .
Despite the 31% protective efficacy observed in RV144 and the lack of protection in Vax003, NAb responses were lower in RV144 than in Vax003 [98▪]. 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 , whereas ALVAC (vCP1452) prime and gp120 MN in alum boost elicited lower IgG4 relative to IgG1 and IgG3 antibodies . Antigen-specific IgG3 antibodies have been associated with control of the pathogen and clinical protection in several infectious diseases [130–132]. A comparative study of IgG subclasses between RV144 and Vax003 may provide additional clues to mechanisms of vaccine protection.
The Step (HVTN502) [107▪▪] and Phambili (HVTN503)  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 . This virus sieve analysis suggests that there were vaccine-elicited T-cell responses potentially not picked up by the interferon-gamma (IFN-γ) ELISpot assays, and that vaccine-elicited Gag and Nef-specific CD8+ T cells  applied pressure to the virus resulting in specific escape mutations in those with specific human leukocyte antigen (HLA) alleles. Moreover, vaccinees with HLA alleles associated with HIV-1 control had a significantly lower mean viral load over time . 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 . Very recently, HVTN 505 was stopped for futility, showing no efficacy and no statistically significant effect on viral load as well as a nonsignificant increase in the number of HIV infections among vaccine recipients compared with the placebo group (Table 2). Similarly, a recent follow-up analysis of HVTN503 participants suggests a nonsignificant increased rate of HIV infection in the vaccinees compared with placebo recipients . 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.
Table 3 shows some of the clinical trials planned within the next 5 years on the basis of lessons learned from recent trials.
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 [135–138]. This work is being based on study of envelope structure and host–pathogen interactions aimed at guiding the immune response towards 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 [139▪]. 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 . 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 . Several studies in nonhuman primates have reported the elicitation of mucosal immunity by different vaccine regimens (reviewed in ). Interestingly, a gp41-derived peptide formulated on virosomes protected macaques against simian human immunodeficiency virus challenge and elicited mucosal IgA and IgG antibodies in the protected animals . The same vaccine administered in humans via systemic and mucosal routes elicited limited IgG and IgA antibodies in mucosal secretions . 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  and conserved sequences  are promising avenues. Alternative vectors that might minimize or eliminate the presence of pre-existing antivector immunity  such as rare serotype human  and chimpanzee [148,149] adenovirus vectors as well as replication-competent vectors  are now in early clinical development (Table 3). 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 Africa 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 [151–153], which will demand similar efforts in the future. Although heterosexual transmission predominates in sub-Saharan Africa , an epidemic in MSM is now expanding [155,156]. MSM will represent the predominant high-risk population for future HIV-1 vaccine efficacy trials in Asia [157–159]. The feasibility of efficacy testing in IDU is questionable due to the success of harm reduction programmes  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 .
Adaptive trial designs that would allow for the ongoing comparative evaluation of multiple vaccine concepts have been suggested as a way to inform immune correlates analysis and enhance the efficiency of efficacy evaluation of HIV-1 vaccine candidates . They may also help address the complexities of evaluating the efficacy of multiple HIV prevention measures in combination [163,164].
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 modelling, interdisciplinary teams and strong international collaborations.
We are extremely grateful to the HIV-1 vaccine trial volunteers and their supporting communities whose willing participation in vaccine clinical trials has greatly advanced the field.
The opinions herein are those of the authors and should not be construed as official or representing the views of the U.S. Department of Defense (DOD) or Department of the Army.
Conflicts of interest
These studies were supported in part by an Interagency Agreement Y1-AI-2642-12 between U.S. Army Medical Research and Materiel Command (USAMRMC) and the National Institutes of Allergy and Infectious Diseases. In addition, this work was supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. DOD.
There is no conflict of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 514).
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clinical trial; correlates; efficacy; HIV-1; vaccine
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