I am pleased to have this opportunity to write a preface for this special issue on
behalf of the journal “AIDS Research and Therapy”. My research team within Imperial
College London (UK) and the European AIDS Vaccine Initiative 2020 (EAVI2020) that
I co-ordinate have long-term collaborations with HIV researchers in Canada, and I
was invited to attend the Canadian HIV Vaccine Workshop supported by Canadian HIV
Vaccine Initiative (CHVI) in Ottawa in December 2016. I was deeply impressed by the
success and achievements made by the Canadian HIV vaccine research community. The
workshop highlighted the ability of Canadian researchers to make unique contributions
in the HIV vaccine research field.
Current status of HIV vaccine research in the world
HIV vaccine development is one of the greatest biological challenges of our generation.
Overcoming viral diversity is a major issue, but many additional challenges will need
to be addressed before an effective vaccine can be successfully formulated to achieve
the necessary levels of protection required. For example, broadly neutralizing anti-HIV
antibodies (bNAbs) that arise during natural HIV-1 infections often take several years
to develop and tend to have unusual features which are likely to pose challenges for
elicitation through vaccination. These include high levels of somatic mutation, autoreactivity
with self-proteins, and long complementarity determining regions [1]. For antibody
induction, it is critical that the field better understands the structure of the native
Env trimer and the role of the glycan shield in antibody interactions [2–4]. While
the induction of bNAbs remains a key goal of HIV research, increasing emphasis is
being placed on additional antibody functions beyond classical neutralization including
Antibody Dependent Cytotoxicity (ADCC) and phagocytosis (ADCP). While there is much
debate over the protective utility of these functions in the absence of neutralization,
it is clear they have potential to augment neutralizing activity. Exploiting such
mechanisms may enhance the potential efficacy of vaccine candidates. Indeed, two vaccine
strategies in late stage efficacy trials are solely dependent on the elicitation of
antibodies that only function through FcR mediated mechanisms and display little appreciable
neutralization [5]. These studies will prove key in testing whether such functions
by themselves are capable of mediating effective protection in individuals at high
risk of HIV infection. While development of a prophylactic vaccine remains the primary
goal of vaccine research, a renewed interest has been placed on the role of vaccines
in effecting long-term remission (effective “cure”) for HIV infected individuals,
reducing the need for life-long medication [6]. A desirable long-term goal is to merge
parallel B cell and T-cell focused vaccine strategies into an immunological “one-two
punch”. This combined approach would incorporate vaccine elements that enable elicitation
of antibodies that effectively block infection, coupled with elements that elicit
favorable T-cell responses to provide immune-mediated control of breakthrough infections.
Without question, the development of a successful HIV vaccine is a sophisticated task
and needs collective global effort.
The current HIV vaccine research in Canada
In the last several decades, Canadian researchers have made significant contribution
to HIV vaccine development. Several Canadian researchers have developed their own
unique anti-HIV vaccines. For instance, Dr. Yong Kang from UWO, recently tested his
whole-killed HIV vaccine (SAV001), in a phase 1 human clinical trial. The vaccine
preparation was genetically modified by deleting the nef and vpu genes and fully inactivated
by aldrithiol-2 and γ-irradiation [7] while his collaborator, Dr. Yong Gao (UWO) has
developed a polyvalent anti-HIV vaccine by utilizing multiple different HIV-1 subtype
strains [8]. The Gao lab has found that sequential vaccination strategy could generate
broad humoral immune responses (able to neutralize HIV-1 subtype A, B, C and D strains)
in a human CD4 B cell transgenic model. Continuing on the theme of invoking a strong
humoral response, Drs. Trina Racine, Gary P. Kobinger (UL), and Eric J Arts (UWO)
are now working with International AIDS Vaccine Initiative (IAVI) in developing a
VSV-based HIV vaccine [9] that will combine unique Canadian research on the HIV-1
Env glycoprotein and on the VSV vaccine vector with the goal of developing a vaccine
with a robust and potent anti-HIV immune response with an emphasis on generating quality
antibodies to protect against HIV challenge. Again success of any humoral-based vaccine,
is dependent of neutralizing antibody production as well as Abs that elicit ADCC.
Dr. Andres Finzi (UOM) has been studying how the structural properties of HIV-1 Env
might have contributed to the modest efficacy of the RV144 trial and has recently
used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected
cells to ADCC by easy to elicit non-neutralizing Abs [10].
Segwaying into the role immune cell interactions for optimal anti-HIV responses, Dr.
Mario Ostrowski (UOT) has evaluated a number of new adjuvants, such as tumor necrosis
factor superfamily (TNFSF) molecules, toll-like receptors (TLRs) agonists, and nucleotide-binding
oligomerization domain-containing proteins (NODs) agonists in order to elicit and
then maintain a durable and potent memory response from B cells, CD8+ T cells, and
NK cells, but avoid overstimulation of HIV-1 susceptible CD4+ T cells [11]. Dr. Dikeakos
also attempts to develop HIV-1 nef inhibitors as specific adjuvants [12]. Dr. Ma Luo
(UOM) is trying to develop vaccines inducing a T cell response to the highly conserved
sequences surrounding the protease cleavage sites (PCS) with the aim of disrupting
viral maturation, while limiting excessive immune activation [13]. Variation in epitopes,
possible like PCS, could confer resistance but Dr. Michael Grant (MU) has also shown
that sequence variants of native immunogenic peptides (termed ‘heteroclitic’ peptides)
can generate more robust CD8+ T cell responses and may steer responses away from the
phenotypic and functional attributes of exhaustion acquired during chronic HIV infection
[14]. As reported by Dr. Larijani [15] sequence changes in epitopes can be induced
by APOBEC3G (A3G) and APOBEC3F (A3F)-induced mutations when can effectively diminish
CTL recognition. Collectively, these various avenues of vaccine investigation will
contribute invaluable and novel information in the design of newer and improved HIV
vaccines.
Aside from the preventative vaccines, another important focus to HIV research relates
to finding latent HIV in patients receiving cART and how to eradicate this HIV to
cure an ongoing infection. Canada has two strong groups of researchers funded by a
Gates Foundation-CIHR join intiative. The The Canadian HIV Cure Enterprise (CanCURE)
led by Dr. Eric Cohen is focused on finding the elusive latent HIV pool in myeloid
cells as well as engaging HIV accessory proteins to find/activate/kill the hidden
virus. Dr. Hugo Soudeyns coordinates the Early Pediatric Initiation, Canada Child
Cure Cohort Study (EPIC4) that is identifying and enrolling HIV infected infants and
then providing possible cure strategies. Infants remain an HIV population where a
cure may be most feasible. For HIV infected adults and possibly infants receiving
effective treatment, Dr. Jamie Mann (UWO) described a new “Kick and Kill” approach
to eradicate the established proviral reservoir in HIV patients by utilizing an autologous
virus-like-particle therapeutic vaccine [16]. Dr. Kaufmann has set up a novel RNA
Flow cytometric fluorescent in situ hybridization (FISH) to detect cytokine mRNA and
corresponding protein in single cells for investigations into HIV immunology, vaccination
and cure strategies [17].
In parallel to vaccine design efforts other Canadian researchers have been instrumental
in studying the mechanisms governing mucosal transmission and susceptibility to infection.
Dr. Rupert Kaul (UOT) has provided evidence that the genital microbiome may be an
important driver of immune activation in adjacent foreskin tissues while altering
this microbiome may be of significant benefit to HIV prevention [18]. To maximize
vaccine efficacy, Dr. Jean-Pierre Routy (MGU) proposed that interventions to reduce
inflammation might be advantageous at increasing protective HIV vaccine responses
by reducing the basal risk of HIV transmission [19]. Innate cellular immunity still
remains our first line of defence and Dr. Nicole Bernard has found that an important
component of the anti-viral activity of stimulated NK cells that secretion of CC-chemokine
(e.g. CCL4) can block HIV entry into new CD4+ target cells [20]. Dr. Keith Fowkes
describes a new concept in prevention where instead of targeting the virus, they modulated
the host immune system (i.e. mimicking the immune quiescence phenotype) to resist
HIV infection [21]. Dr. Kaushic has studied the influence of common mucosal co-factors
on HIV infection in the female genital tract, and discussed the role of hormonal contraceptives
and bacterial vaginosis on tissue inflammation, T cell immunity and HIV susceptibility
[22]. These approaches will be highly valuable for the future development of multi-purpose
interventions to prevent HIV transmission and may help to maximize the protective
efficacy of novel vaccines.
Suggestions for further improving HIV vaccine research in Canada
Canadian Federal Government funding towards the development of an HIV vaccine through
CHVI (Canadian HIV Vaccine Initiative) has helped to cultivate a Canadian HIV vaccine
community with internationally recognized strengths capable of making major contributions.
The keen interest shown by IAVI and EAVI to involve Canadian researchers is clear
evidence of their ability to make unique contributions. No one country can create
a successful vaccine due to prohibitive costs of translational vaccine studies for
country-specific funding organizations and the need for centralized facilities, such
as transgenic animal models, humanized mouse models, non-human primates, certified
good manufacturing practices (GMP), and other expensive infrastructure and resources.
Fortunately, these facilities and resources key to vaccine development and testing
are available to these multination collaborations largely funded by the Gates Foundation,
the US and European funding bodies. It is also critical to maintain a two-pronged
approach directing strategic funding towards specific areas where translational progress
was most likely, while maintaining support for innovative projects that address unresolved
basic and social research issues.
I hope that this special issue will act as a positive signal to government decision
makers, indicating that in-roads are being made in HIV vaccine discovery, to the international
scientific community that Canadian HIV vaccine research is multifaceted and impactful,
to the general public that HIV research is strong in Canada, and more importantly,
to communities blighted by HIV, that important scientific advances are being made
on multiple fronts. Indeed, as increasing public support is a critical component of
advocacy, efforts and accomplishments of the Canadian HIV vaccine research community
should be highlighted to a much greater extent at community, funding agency, media
and elected government official level.