Adenoviruses are common in nature and are a major cause of
severe colds. During the past decade, attenuated forms of adenovirus have
become increasingly utilized as experimental vaccine vectors due to their
targeting of dendritic cells and ability to induce CD8 T cell responses in the
majority of recipients (no other vector to date has shown comparable CD8 T cell
immunogenicity). Adenoviruses are categorized into a number of different
serotypes, with serotype 5 (Ad5) being among the most prevalent. An HIV vaccine
candidate that used Ad5 as a vector was developed by Merck, but failed to show
efficacy and significantly enhanced HIV acquisition risk in a subset of trial
participants with pre-existing antibody responses against natural Ad5.
Since the Merck data were published, there has been debate
about the mechanism by which the Ad5 vector could have increased the risk of
HIV acquisition, and even claims that the result was a statistical fluke or
represented a confounding effect related to circumcision status (the former
claim is possible, the latter was contradicted by a multivariate analysis showing
that both lack of circumcision and receipt of the Ad5 vaccine were associated
with an increased likelihood of HIV acquisition). Perhaps most controversially,
it has been suggested that perhaps the Merck vector boosted Ad5-specific CD4 T
cell responses, thus providing more activated CD4 T cell targets for HIV
infection. Two studies that measured Ad5-specific CD4 T cell responses in
recipients of the Merck vaccine based on cytokine production have argued
against this possibility (see here and here), while another that assessed Ad5-specific CD4 T cell responses based on their ability to proliferate suggested that CD4 T cell-mediated
enhancement could have played a role.
Lurking on the sidelines of this contentious debate has been
the issue of natural adenovirus infection, about which relatively little is
known. Now a study by Larry Corey’s research group, published recently in PLoS
One, has for the first time evaluated natural adenovirus infections among one
of the populations enrolled in the Merck HIV vaccine trial, Peruvian men who
have sex with men (MSM).
The results are perhaps surprising: the majority of the 20
men studied had detectable adenovirus DNA in rectal swabs during follow-up; the
average rate of detection at any given timepoint was in 30% of samples. A
variety of adenovirus serotypes were represented, including Ad5, Ad26 and Ad48,
all of which are in development as vaccine vectors. The study authors note
that: “shedding typically occurred on consecutive days in clustered episodes
lasting a median of 4 days (range 1 to 9 days) separated by periods without
shedding, suggesting frequent new infections or reactivation of latent
infections over time.”
The study raises a number of issues. First and foremost, it
suggests that when a pathogen is being developed as a potential vaccine vector,
a thorough understanding of the natural infection should be obtained early on
in the research process, and not after the fact. In the case of adenovirus vectors, their success in solving
the difficult problem of inducing CD8 T cell responses may have caused the lack
of information on natural infections to be somewhat overlooked. In terms of
specific relevance to the Merck trial, the study implies that interactions
between adenovirus-specific immunity and natural adenovirus infections are
likely to be far more dynamic and ongoing than had previously been surmised.
The boosting of Ad5-specific CD4 T cell responses by vaccination might
therefore have different consequences depending on whether natural adenovirus
infection is present, particularly given that the virus localizes in the mucosa
and Ad5-specific CD4 T cell responses cross-react with a wide variety of
serotypes. Additional studies will now be needed to investigate the impact of adenovirus-based
vaccines on mucosal virus-specific CD4 T cell responses in the presence and
absence of natural infection.
PLoS One. 2010 Jun 25;5(6):e11321.
Curlin ME, Huang ML, Lu X, Celum CL, Sanchez J, Selke S,
Baeten JM, Zuckerman RA, Erdman DD, Corey L.
Fred Hutchinson Cancer Research Center, Seattle, Washington,
United States of America.
Abstract
BACKGROUND: The association between baseline seropositivity
to human adenovirus (HAdV) type 5 and increased HIV acquisition in the Step HIV
Vaccine Study has raised questions concerning frequency of acquired and/or
persistent Adenovirus infections among adults at high risk of HIV-1 infection.
METHODOLOGY: To evaluate the frequency and pattern of HAdV shedding from the
lower GI tract, we retrospectively tested rectal swabs for HAdVs in a cohort of
20 HSV-2 positive HIV-positive Peruvian men who have sex with men (MSM)
undergoing rectal swabbing three times/week for 18 consecutive weeks, in a
prospective study of HSV-2 suppression in HIV infection. Viral DNA was
extracted and amplified using a sensitive multiplex PCR assay that detects all
currently recognized HAdV types. Molecular typing of viruses was performed on
selected samples by hexon gene sequencing. Baseline neutralizing antibody
titers to HAdVs -5, -26, -35 and -48 were also assessed. PRINCIPAL FINDINGS:
15/20 individuals had HAdV detected during follow up. The median frequency of
HAdV detection was 30% of samples (range 2.0% to 64.7%). HAdV shedding
typically occurred on consecutive days in clustered episodes lasting a median
of 4 days (range 1 to 9 days) separated by periods without shedding, suggesting
frequent new infections or reactivation of latent infections over time. 8 of
the 15 shedders had more than one type detected in follow-up. 20 HAdV types
from species B, C, and D were identified, including HAdV-5, -26 and -48, HAdV
types under development as potential vaccine candidates. 14/20 subjects were
seropositive for HAdV-5; 15/20 for HAdV-26; 3/20 for HAdV-35; and 2/20 for
HAdV-48. HAdV shedding did not correlate with CD4 count, plasma HIV-1 viral
load, or titers to HAdV-5 or HAdV-35. The sole individual with HAdV-5 shedding
was HAdV-5 seropositive. CONCLUSIONS: HAdV shedding was highly prevalent and
diverse, including types presently under consideration as HIV vaccine vectors.
Subclinical HAdV infection of the GI tract is common among MSM in Peru; the
prevalence of HAdV in the enteric tract should be evaluated in other populations.
The association between ongoing recent enteric HAdV and the immune response to
recombinant HAdV vaccines should be evaluated.
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