By
Liz Highleyman
Investigators with the U.S. Military HIV Research Program
(MHRP) announced
in late September that a Phase 3 trial of more than
16,000 participants in Thailand found that an ALVAC-HIV
primer vaccine followed by an AIDSVAX B/E booster reduced
the risk of HIV infection by about 30%. The findings were
widely hailed in the media as being the first evidence that
a vaccine could prevent HIV in humans, after years of disappointing
results.
In
the RV144 trial -- the largest HIV vaccine study ever conducted
in humans -- 16,402 initially HIV negative men and women
aged 18-30 years were randomly assigned on a 1-to-1 basis
to receive either the vaccine combination (4 doses of ALVAC
followed by 2 doses of AIDSVAX) or placebo injections. Both
genetically engineered vaccines carry genes from HIV strains
prevalent in Southeast Asia.
Injections
were administered within a 6-month period and participants
were then followed for an additional 3 years, receiving
HIV testing and prevention counseling every 6 months. The
researchers looked at whether participants became HIV infected,
and whether those who did seroconvert had lower viral loads.
Results
were reported at the Paris conference and published the
same day in the October
20, 2009 advance online edition of the New England Journal
of Medicine.
Results
 |
In an intention-to-treat analysis of all 16,402 participants,
there was a trend toward prevention of HIV infection
among vaccine recipients, with an efficacy of 26.4%: |
| |
|
56
vaccine vs 76 placebo recipients infected; |
|
95%
confidence interval (CI): -4.0 to 47.9; very wide,
indicating considerable uncertainty; |
|
P
= 0.08; a value < 0.05 is generally used as
a cut off for statistical significance. |
|
|
In
a modified intention-to-treat analysis involving 16,395
participants, excluding 7 people who were determined
to have been already HIV-infected at study entry, the
vaccine efficacy was 31.2% -- the figure reported in
September: |
| |
|
74
vaccine vs 51 placebo recipients infected; |
|
95%
CI: 1.1 to 51.2; |
|
P
= 0.04, just reaching statistical significance. |
|
|
In a per-protocol or "as treated" analysis
involving 12,452 participants who received all vaccine
doses as scheduled, the vaccine efficacy was 26.2%: |
| |
|
36
vaccine vs 50 placebo recipients infected; |
|
95%
CI: -13.3 to 51.9. |
|
P
= 0.16, no longer close to borderline significance. |
|
|
The
vaccine appeared to provide the greatest protective
effect during the first year (about a 60% decrease in
infection risk). |
|
Heterosexual
participants at low or medium risk for infection appeared
to derive more benefit from the vaccine than high-risk
participants such as men who have sex with men, injection
drug users, or sex workers (about a 40% risk reduction
for low-risk, 47% for medium-risk, and 4% for high-risk
recipients). |
|
Vaccination
did not affect viral load levels or CD4 cell counts
in participants who became infected. |
|
The
vaccine combination was generally well-tolerated, with
no serious safety concerns identified. |
"This
ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the
risk of HIV infection in a community-based population with
largely heterosexual risk," the investigators concluded.
"Vaccination did not affect the viral load or CD4+
count in subjects with HIV infection. Although the results
show only a modest benefit, they offer insight for future
research."
"This
is the first evidence that a prime-boost HIV vaccine regimen
may prevent infection and represents a significant step
forward for vaccine research," Colonel Nelson Michael,
Director of the U.S. Military HIV Research Program, said
in a press statement. "While it will not likely have
any immediate public health benefit, we are hopeful that
the findings will guide additional studies and accelerate
research efforts toward a more effective vaccine."
The
initial presentation of the modified intention-to-treat
result -- the only one to reach statistical significance
-- ahead of the others garnered considerable criticism after
the less impressive data was revealed in Science magazine's
Science Insider blog earlier this month.
While
a complete intention-to-treat analysis is generally considered
the most rigorous, Colonel Michael argued that the modified
analysis was appropriate for this trial. "Given that
you cannot protect someone from an infection that they already
have acquired, the modified intent-to-treat analysis excluded
these individuals," he said, noting that all 3 types
of analysis were planned, not ad hoc. Full results
were not released in September due to policies about "embargoes"
on findings prior to publication or presentation at a conference.
"The
trial raises more questions than it answers," Alan
Bernstein of the Global HIV Vaccine Enterprise, one of the
sponsors of the Paris conference, told Bloomberg news. "The
initial protective effect after the first year looked like
it was 60 percent and it dropped off with time. The most
important thing with vaccines is memory."
"Perhaps
the requirements for protection against transmission in
low-risk, heterosexual persons are considerably different
or less stringent than those in high-risk subjects,"
wrote Raphael Dolin of Beth Israel Deaconess Medical Center
in an editorial accompanying the New England Journal
of Medicine report.
The
ambiguity of the RV144 findings -- and a preliminary announcement
that many regarded as overly hyped -- have deepened the
debate about the ethics and cost-effectiveness of pursuing
HIV vaccine research of this type. The purported protective
effect of the ALVAC/AIDSVAX combination was particularly
unexpected, since both component vaccines have shown no
benefit when used alone.
The
researchers plan to conduct more in-depth studies of blood
samples from a smaller subset of vaccine recipients in an
attempt to learn more about the "correlates of protection,"
or differences in immune cell activity and other biological
markers in vaccinated individuals.
"The
establishment of such correlates is the central question
in HIV vaccine development and will have a profound effect
on the designs of vaccines and clinical trials to assess
their efficacy," Dolin wrote in his editorial. "Given
the lack of detection of conventional immune responses in
earlier studies of these vaccine components, as well as
the divergence between the vaccine's effect on the infection
and the effect on viral load, the correlates of protection
may, indeed, reflect new concepts of host response. This
should be the focus of intense research using the most current
research techniques. Ultimately, it is the results of such
studies that will most likely determine the significance
of this clinical trial to the field of HIV vaccine development."
"This
is a weak signal, but a signal that has enough relevance
that we need to
pursue it," said National Institute of Allergy and
Infectious Diseases director Anthony Fauci.
10/23/09
References
S
Rerks-Ngarm, P Pitisuttithum, S Nitayaphan, and others.
Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection
in Thailand. New England Journal of Medicine. October
20, 2009 (Epub ahead of print). Free
full text.
R
Dolin. HIV Vaccine Trial Results -- An Opening for Further
Research. New England Journal of Medicine. October
20, 2009 (Epub ahead of print). Free
full text.
Other
Sources
U.S.
Military HIV Research Program. Detailed Results from RV
144 HIV Vaccine Trial Published Today in The New England
Journal of Medicine and Presented at the AIDS Vaccine 2009
Conference Provide Insight for Future Research. Press
release . October 20, 2009.
S
Bennett and MF Cortez. AIDS
Vaccine's Benefit May Wane After First Year. Bloomberg.com.
October 20, 2009.
J
Cohen. Unrevealed
Analysis Weakens Claim of AIDS Vaccine "Success."
Science Insider. October 5, 2009.
