Rapporteur reports
Track A: HIV Basic Science report by Eric Arts
Neutralising Antibodies - Burton
Dr. Denis Burton provided a detailed and comprehensive summary on the
efforts in developing neutralizing antibodies with attempts to improve
specificity and levels in patients but more importantly, to identify
proper immunogens. Three immunogens are being developed: 1)
trimer mimics of gp120/gp41 have been largely unsuccessful because of
incorrect or inappropriate folding of recombinant proteins, 2) entry
intermediates are being develop to expose the co-receptor binding site,
and 3) epitope mimics use broadly neutralizing antibodies as template
for future immunogens. In regard to the third strategy, there are
several neutralizing Abs that can serve as good candidates. The
anti-gp120 B12, which binds to the CD4 binding-site may be the most
developed due in part to the recent crystal structures by Kwong et
al. Others include 2F5 and 4E10, which block co-receptor usage
but when this epitope was introduced in the correct "immunogen"
orientation in the V1V2 loop of env, it did not elicit neutralizing Abs
in mice. Obviously, the presentation of the conserved motifs in
gp120 will continue to be challenge but if conquered, could have great
benefit for future vaccine strategies.
Vector Based Vaccines - Pantaleo
There are several different ways to immunize against HIV viral
proteins, but the most promising is to incorporate sequences for these
HIV proteins into other, non-pathogenic viruses. Candidate viruses
include adenoviruses, particularly Ad5 serotype, and attenuated
vaccinia virus strains. In many trials currently underway, the viral
vectors are used after initial immunizations with naked DNA that also
include HIV sequences. Ad5 has a number of advantages and Trivalent Ad5
Vaccine from Merck has proved to be highly immunogenic, inducing
long-lived cellular immunity. Another candidate vaccine, the
recombinant Ad5 vector from the Vaccine Research Centre at the NIH, is
also highly immunogenic, particularly inducing responses to env.
However, Ad5 vectors may be limited by pre-existing neutralizing
antibodies in the community, especially in Africa. Vectors based on
other adenovirus serotypes may lead to enhanced immunogenicity.
Attenuated vaccinia strains, such as NYVAC, are also promising vectors,
and in the EuroVacc 02 Trial, were highly immunogenic for incorporated
HIV proteins. Not only were responses long-lived, but qualitatively,
they induced CD4 and CD8 T cells which produced IL-2, IFN-gamma and
TNF-alpha, were cytotoxic and proliferated in vitro, all of which are
correlates of control of HIV infection.
Correlates of Immunity - Walker
Control of HIV replication in vivo correlates with the number of gag
epitopes recognized. Surprisingly, recognition of an increasing number
of envelope epitopes is associated with higher viral load. Similar
observations have been made when studying T cell clones in vitro.
Gag-specific T cell clones strongly inhibit HIV replication in vitro in
7-10 day cultures, whereas env-specific clones are much less effective.
This did not appear to be due to appearance of escape mutants. This CD8
“neutralization” was not correlated with ELISPOT activity, and appears
to be measuring a different activity, possibly dependent on antigen
processing. In the case of gag processing, the pre-existing molecules
in the incoming virion can be a source of antigen 24 hours before new
viral antigen synthesis.
These results raise the possibility that gag epitopes may be the most
effective targets for vaccines in vivo. Whether these in vitro results
using cells from chronically infected individuals really apply to
generation of new responses is unknown. Furthermore, the CD8
“neutralization” assay is not really feasible in field vaccine trials,
but should be considered in small numbers of individuals.
Track B: Clinical Research, Treatment and Care report by Sarah Pett
This session is also covered in track A. Glenday Gray gave an overview of the ongoing phase IIb vaccine studies. The current portfolio of vaccines are expected to illicit CTL responses only. These responses may prove beneficial even if they do not prevent infection. Secondary impacts may include slower rates of HIV progression (via lower viral load set point), less HIV transmission, increased durability of the T-cell response, and prolongation of the time to ART initiation. Two of these studies (STEP study in USA, latin America, Caribbean, Australia, n=3000) and the HVTN503 study in South Africa are using the Merck Ad5 vector vaccine (directed against clade B). These studies have two co-primary endpoints, number of new HIV infections on study and changes in viral load.
Dennis Burton gave an overview of anti-HIV neutralising antibodies. There are two key issues, first, which antibodies neutralise and what levels are beneficial and second, how do we provide immunogens that illicit their production in vivo. Three strategies have been developed: trimeric mimics, entry intermediates and epitope mimics. Targets have included the CD4+ binding site of HIV as this is highly conserved and the glycan shield.
Giuseppe Pantaleo gave an overview of vector-based vaccines (all are replication incompetent) i.e. using adenovirus (subtpe Ad5) and pox virus vectors focussing on some of the new strategic approaches to overcoming the problems of vaccine ‘take” in those with pre-existing high levels of antibodies to Ad5. These include, novel serotype rAd vectors and chimaeric r-Ad. Replication competent vectors i.e. adenovirus, pox viruses and measles are in pre-clinical development.
Bruce Walker gave an overview of the correlates of immunity and suggested that many of the current assays that are used to assess vaccines do not necessarily reflect a function that is associated with reducing viral replication. He described virus neutralisation assays in which CTL responses that neutralised virus replication could be defined in vitro. These assay systems were able to elucidate which cells were neutralising viral replication i.e. potent with gag KK10-sepcific T-cells and were able to accurately measure immune escape. He went on to describe a series of experiments exploring whether the breadth of virus neutralisation by CTL depended on the epitopes targeted. The breadth of gag epitopes was associated with a lower viral load, in contrast the breadth of env epitopes was associated with higher viral load. These experiments need to be explored in vivo, but these results may have important implications for vaccine development.
Track C: Biomedical Prevention report by Nick Walsh
Ultimately an effective vaccine is the goal HIV research is seeking. So how far along the road are we?
Glenda Gray began by reviewing what we can learn from research around seroconversion and the natural history of early HIV infection - the implications for vaccine research and developing relevant endpoints for phase 3 vaccine trials. Endpoints need to be clinical and viral, preventing both primary infection and the progression of HIV disease.
Dennis Burton reviewed progress in the development of broadly neutralising antibodies to HIV. He discussed immunogens that target MPER (4E10, 2F5, Z13e1), the CD4 binding site (b12) and the glycan shield (2g12). Although these are potential candidates work is in the early stages and adequate immunogenicity remains a problem.
In contrast to early work in vaccines that focus eliciting humoral immunity, vector based vaccines inducing an innate immune response have progressed to phase 1 and 2 trials. Guiseppe Pantaleo review the development of these. The adenovirus Ad5 is the most common vector used due to its high safety and immunogenicity. Trivalent Ad5 Vaccine has shown reasonable sustained immunogenicity in phase 1 trials though it will be necessary to boost immunogenicity by DNA prime or other rarer serotypes such as rAd26. Poxviruses are also safe and can induce cell mediated and humoral responses. EuroVacc 02, which seeks to evaluate a poxvirus based vaccine candidates DNA-HIV-C alone and of the prime-boost regimen of DNA-HIV-C+NYVAC-HIV-C, and to compare the immunogenicity of the prime-boost regimen to NYVAC-HIV-C alone in healthy volunteers at low risk of acquiring HIV infection. Phase 1 data suggests a durable and function response against HIV-1.
So how can we measure functional immunity in vaccine research? Perhaps in-vitro research should look at infected cells, rather than peptides. Bruce Walker explored mechanisms to quantitate HIV neutralization ability of cyotoxic T lymphocytes (CTL), in theory a more physiological relevant response. When measured using this technique Gag-epitope specific enrichment results in greater viral neutralisation compared with Env epitopes. Ultimately the question is should we be measuring CMI responses as part of evaluating HIV vaccine candidacy.
Key themes from the session were that although there are vaccine candidates available, those focusing on cellular immunity are further progressed than those focusing on humoral immunity.
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