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Posted: 16 Dec 2011
Journal Club: Is a T cell vaccine still a likely goal?
Author: Hayley Crawford

In this week's Journal Club, Hayley Crawford ponders on the implications of correlates analysis of the RV144 trial results and goes over recent data on immunogenicity of several T-cell vaccines.


At AIDS Vaccine 2011 in Bangkok, Thailand, Barton Haynes presented results from the immune correlates study performed on subjects from the Thai RV144 trial. For those of you who have spent the past 2 years under an ice bucket, this trial tested an ALVAC prime (a canarypox vector encoding gp120-clade E, gp41-clade B, and Gag-Protease-clade B) and an AIDSVAX boost (a bivalent gp120-clades B and E) in over 16,000 HIV-negative volunteers in Thailand. The vaccine was safe and 31.2% effective at preventing HIV infection. While this figure appears low, it is encouraging and a step in the right direction: it’s the first trial to demonstrate fewer infections in the vaccine group than in the control group (click here for details).

In the two years since the initial findings were presented at AIDS Vaccine 2009 in Paris, France, 20 labs around the world have performed analyses on samples from 286 subjects from this trial in order to determine the immune correlates responsible for the reduction in infections.

In Bangkok, Dr. Haynes reported that two immune responses were significantly associated with the HIV infection rate. The first one, IgG antibodies recognising the V1/V2 loop in Env, was associated with a 43% reduction in the infection rate. The second response, IgA antibodies, was associated with a 54% increase in the infection rate. But before we blame IgA for our vaccine woes, take note that this finding suggests only that IgA may interfere with protection against HIV infection, as no indication of enhancement of infection has been found for the vaccine arm.

Only one of the six primary assays used in the search for correlates of protection focused on cellular immune responses: the measurement of intracellular cytokines in CD4+ T cells. But the results there showed not much difference, and were far from significant. There are, however, secondary assays currently in progress, and these include more cellular assays. One early finding is inspiring: there was a ~60% reduction in infection rates in subjects with medium to high levels of cytokines secreted by PBMCs (Figure 1). Does this give cellular immunity a starring role alongside the vaccine fan’s favourites, antibodies?


Figure. 1. Slide from Barton Haynes’ presentation at AV2011, showing an association between medium/high PBMC cytokine levels and a ~60% decrease in probability of acquiring infection.

Let’s take a look at recent studies on developing and testing the immunogenicity of T cell vaccines:

Studies from Mariano Esteban’s group in Barcelona, Spain, published recently in both Vaccine (Garcia et al., 2011) and Journal of Virology (Gomez et al., 2011), tested an MVA-B vaccine, containing Env, Gag, Pol and Nef. This construct, intended to be a therapeutic vaccine, elicited T cell responses (predominantly Env-specific) in 75% of vaccinees, and antibodies in 95%. Neutralizing antibodies were detected in 33% of vaccinees. However, before your high percentage-centric excitement bubbles over, it’s worth mentioning that the study numbers were extremely small: there were only 30 participants in the study, and 6 of those were given placebo shots. Plus, only one clade was researched: clade B.

Another vaccine regimen displaying good immunogenicity, if Env-specific CD4+ are what you’re after, is a PENNVAX-G DNA prime (gp120-A/C/D, gag-A/B/C/D), MVA-CMDR boost (env/gag/pol-CRF01_AE) from the United States Military HIV Research Program in Rockville, Maryland. The immunogenicity of the MVA-CMDR component was described in a paper published in PLoS ONE last year (Currier et al., 2010) by this group, looking at 48 HIV-negative low-risk subjects. Env-specific CD4+ T cells were invoked in 100% of subjects, Env-specific CD8+ T cells arose in 30% of subjects, while 40% of subjects had Gag-specific CD8+ T cells. Importantly, these responses were durable: lymphoproliferative response rates (an increase in T cell production) were at 100% in the intramuscular groups at six months (Figure 2).

Figure 2. Lymphocyte proliferation responses for each dose and route. An increase in the production of lymphocytes was seen in 100% of vaccines post-vaccination (red dots). A higher response to gp140 was observed, compared to p24 (A & B); and the magnitude of the response was route-dependent: the intramuscular (IM) route stimulated more than the intradermal (ID) route. Cross-reactivity of the T cells was shown by stimulation with WIV (whole inactivated virus) antigen (C & D).   (Currier et al, 2010).

Jeffrey Currier presented data on the subsequent PENNVAX-G DNA prime/MVA-CMDR boost trial at AIDS Vaccine 2011. His team found that the prime/boost, delivered either by needle-free intramuscular injection or in vivo intramuscular electroporation, had very similar results to the MVA-CMDR alone: 100% and 45% of subjects had Env-specific CD4+ and CD8+ T cells, respectively, and 55% and 18% had Gag-specific CD4+ and CD8+ T cells, respectively. The CD8+ responses were predominantly effector memory cells, which act immediately and are important controllers of early HIV infection.

Rama Amara’s team at Emory University, Atlanta, Georgia, compared Adenovirus (Ad)-5 and MVA as vaccine vectors, and published their findings in Vaccine (Pillai et al., 2011) in July 2011. They found that the Ad-5 construct primed HIV-specific CD8+ effector T cells at rates 6 times higher than MVA, and those cells underwent less contraction (rapid elimination of 90% of effector cells, leaving a memory cell pool) than MVA-primed cells. However, the Ad-5-elicited memory cells were mainly effector memory cells, while the MVA construct resulted in more central memory T cells, and these central memory T cells had higher rates of expansion following a boost. This shows that the vaccine vector strongly influences what responses are elicited, along with the usual suspects of the method of delivery, prior immunity to the construct, insert design, and so on.

These studies describe diverse vaccine constructs and inserts that are extremely immunogenic in terms of eliciting cellular responses, and provide hope that a T cell vaccine could work. But will these responses be broad, long-lasting, and protective in the face of real HIV infection? The proof will be in the prevention study.

About the author: Hayley Crawford recently completed a post-doc with Astrid Iversen at Oxford University, Oxford, United Kingdom, and is currently writing about science on in Baltimore, Maryland.

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