The Quest for an HIV-1 Vaccine—Moving Forward

The Quest for an HIV-1 Vaccine—Moving Forward

The
NEW ENGLA ND JOURNAL
of
MEDICINE
Perspective
november 28, 2013
The Quest for an HIV-1 Vaccine — Moving Forward
Dan H. Barouch, M.D., Ph.D.
Related article, p. 2083
V
accines have historically been the most effective biomedical interventions for controlling
global infectious diseases. The development of a
safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is
therefore a critical research priority. Although other HIV-1 prevention efforts based on behavioral
risk reduction, male circumcision,
topical microbicides, preexposure
prophylaxis, and treatment as prevention have had substantial effects on HIV-1 transmission rates,
it is likely that a vaccine will be
required to end the global HIV-1
epidemic.
The challenges in the development of a prophylactic HIV-1 vaccine, however, are unprecedented
in the history of vaccinology. First,
HIV-1 exhibits tremendous global
genetic diversity as well as mutational capacity that can evade
both humoral and cellular immune responses. The generation
of vaccine antigens that will elicit
immunologically relevant and
broadly cross-reactive immune responses thus represents a major
challenge. Second, HIV-1 rapidly
integrates into the host genome
and establishes a latent reservoir
that cannot be eliminated by conventional antiretroviral drugs or
virus-specific immune responses.
A vaccine will therefore most likely need to induce potent and functional virus-specific antibodies
that block establishment of initial infection, in addition to high
levels of T lymphocytes for virologic control. Third, there are no
known examples of spontaneous
immune-mediated clearance of
HIV-1 infection indicative of natural immunity, and thus the pre-
cise types of immune responses
that need to be induced by a vaccine are not well understood.
Fourth, although a series of broad
and potent neutralizing monoclonal antibodies have recently
been discovered, such antibodies
are induced only in a subgroup
of HIV-1–infected persons after
several years of infection and typically exhibit extensive somatic
hypermutation. No method currently exists to induce such antibodies by vaccination.
Over the past 30 years, only
four HIV-1 vaccine concepts have
been evaluated in clinical efficacy
trials. The relative paucity of such
trials speaks to the tremendous
scientific and logistic challenges
associated with HIV-1 vaccine development. The vaccine platforms
that have been evaluated in efficacy studies have included purified HIV-1 envelope (Env) proteins,
recombinant adenovirus and poxvirus vectors, and plasmid DNA
n engl j med 369;22 nejm.org november 28, 2013
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PERS PE C T IV E
The Quest for an HIV-1 Vaccine
Env glycoprotein trimer
Outer domain
glycan site
Top view
Quaternary V1-V2
glycan site
CD4binding
site
Glycan
shield
Membrane proximal
external region
HIV-1
Structure of HIV-1 and Expanded View of the Envelope (Env) Glycoprotein Trimer.
COLOR FIGURE
Targets of virus­specific neutralizing antibodies are shown, including the quaternary
Draft 5
11/13/13
V1­V2 glycan site, the outer domain glycan site, the CD4­binding
site, and the mem­
Author Barouch
brane proximal external region. From Nabel GJ. DesigningFigtomorrow’s
vaccines.
1
#
N Engl J Med 2013;368:551­60.
Title
vaccines. The first concept that
was evaluated was the AIDSVAX
Env gp120 protein vaccines, which
were tested in two phase 3 efficacy studies in the United States
and Thailand and were reported
in 2003 to have no efficacy in the
populations studied.1,2
The second concept that was
evaluated was an adenovirus serotype 5 (Ad5) vector expressing the
internal proteins Gag, Pol, and
Nef. This vaccine was shown in a
phase 2b efficacy study in North
2074
ME
and SouthDEAmerica
in 2007 to
Malina
Artist
Knoper
have no efficacy
and in fact may
AUTHOR PLEASE NOTE:
have increased
the
riskand type
ofhasHIV-1
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Please check carefully
3
acquisitionIssue
indate
certain
subgroups.
11/28/13
A parallel study involving the
same vaccine in South Africa was
terminated shortly after initiation,
and unblinded follow-up also
showed increased rates of HIV-1
infection in vaccinees.
The third concept that was
evaluated was a prime–boost
vaccine regimen that involved the
canarypox ALVAC vector followed
n engl j med 369;22
nejm.org
by the AIDSVAX Env gp120 proteins. This was a phase 3 study
(RV144) conducted in a low-risk
population in Thailand that
showed in 2009 a 31% reduction
in the rate of HIV-1 acquisition.4
Vaccine-elicited antibodies against
the first and second variable
loops (V1-V2) of Env correlated
with a reduced risk of HIV-1 infection,5 although the applicability of these findings to other
vaccine platforms remains unclear.
The fourth HIV-1 vaccine concept for which clinical efficacy
testing has been completed is described in this issue of the Journal
(see pages 2081–2090). This vaccine was produced by the
National Institutes of Health
(NIH) Vaccine Research Center
and included priming with DNA
vaccines and boosting with Ad5
vectors expressing Env, Gag, and
Pol. The trial was a phase 2b efficacy study (HVTN 505) conducted in the United States in
men or transgender women who
have sex with men. Vaccinations
were halted at the interim analysis in April 2013 because of lack
of efficacy. Although the vaccine
induced both humoral and cellular immune responses in the majority of recipients, the levels of
neutralizing antibodies, nonneutralizing antibodies, and V2specific antibodies were low.
There was, however, no evidence
of increased rates of HIV-1 acquisition among vaccinees, although unblinded follow-up of
participants is still ongoing.
Despite the lack of efficacy,
this study represents an important contribution to the HIV-1 vaccine field. It was a well-designed
study that reached a clear conclusion on which future research
can build. Future HIV-1 vaccine
candidates will need to elicit im-
november 28, 2013
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PE R S PE C T IV E
The Quest for an HIV-1 Vaccine
mune responses that are either
qualitatively different from or
quantitatively superior to those induced by the DNA–Ad5 vaccine.
It also appears that preclinical
evaluation of future vaccine candidates should involve stringent
challenge models, since the DNA–
Ad5 vaccine afforded substantial
protection against challenges with
the easy-to-neutralize simian immunodeficiency virus (SIV) strain
E660 (SIVsmE660) in rhesus monkeys but failed to protect against
the more difficult-to-neutralize virus SIVmac251. In addition, despite the need to offer the best
available HIV-1 prevention meth-
sibility that vaccination strategies
could be developed to induce such
antibodies. Emerging data on the
structure of the HIV-1 Env glycoprotein and the ontogeny of Envspecific B-cell responses have led
to the design of novel immunogens. The impressive virologic
control achieved by virus-specific
T lymphocytes in certain settings has also suggested important new strategies for improving cellular immune responses.
Moreover, preclinical studies involving stringent challenge models have shown that several novel
vaccine candidates have substantially better protective efficacy
There are clear reasons for optimism
in the quest to develop an HIV-1 vaccine.
The modest protection achieved in the RV144
study provides the proof of concept that
an HIV-1 vaccine is in fact possible.
ods to all participants, potentially
including preexposure prophylaxis with antiretroviral drugs, it is
still operationally feasible to conduct rigorous clinical efficacy trials of HIV-1 vaccines.
There are clear reasons for optimism in the quest to develop an
HIV-1 vaccine. The modest protection achieved in the RV144
study provides the proof of concept that an HIV-1 vaccine is in
fact possible. There have also been
major advances in our basic understanding of HIV-1 immunology and virology that inform vaccine design. The discovery of many
new broad and potent neutralizing antibodies to the Env
An interactive
glycoprotein (see diagram
graphic showing
and interactive graphic,
the structure of HIV-1
available with the full text
and targets of neutralizing
of this article at NEJM
antibodies is available
at NEJM.org
.org) has raised the pos-
than previously tested vaccine
regimens.
The HIV-1 vaccine pipeline currently encompasses several concepts that are moving toward
clinical efficacy trials. Vaccine
candidates for which efficacy studies are planned include ALVAC–
gp120 vaccines specifically designed for South Africa and
Thailand, which build directly on
the results of the RV144 study, as
well as novel vaccine regimens
that include poxvirus vectors with
greater potency than ALVAC vectors, alternative serotype adenovirus vectors that are biologically
different from and superior to Ad5
vectors, mosaic antigens that provide improved immunologic coverage of global HIV-1 diversity,
improved Env protein immunogens, and adjuvants with increased
potency. Additional concepts that
have shown considerable promise in preclinical studies include
replicating vaccine vectors, such
as cytomegalovirus vectors, and
novel strategies for generating
broadly neutralizing antibodies,
including stabilized Env trimers
that mimic the native viral spike,
scaffolds that display specific antibody epitopes, and immunogens
designed to stimulate particular
B-cell lineages.
Yet HIV-1 vaccine development
remains slow and challenging. It
is therefore critical to capitalize
now on the wealth of basic scientific advances and the current
pipeline of vaccine candidates to
accelerate the development of an
HIV-1 vaccine. One important lesson from the efficacy studies conducted to date is that the results
of these studies are often surprising. Regardless, both positive
and negative outcomes of clinical
efficacy trials provide critically
important feedback that affects
preclinical and early-phase clinical studies and informs the development of the next generation of
HIV-1 vaccine candidates.
Testing only four HIV-1 vaccine
concepts for clinical efficacy over
the past three decades is insufficient given the scope of the
global HIV-1 epidemic. We clearly need more “shots on goal.” We
should therefore accelerate the
advancement of a diverse series
of novel and promising HIV-1
vaccine candidates into clinical
efficacy trials over the next several years.
Disclosure forms provided by the author
are available with the full text of this article
at NEJM.org.
From the Center for Virology and Vaccine
Research, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston;
and the Ragon Institute of Massachusetts
General Hospital, the Massachusetts Insti­
tute of Technology, and Harvard University,
Cambridge, MA.
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine
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Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2075
PERS PE C T IV E
The Quest for an HIV-1 Vaccine
1. Flynn NM, Forthal DN, Harro CD, Judson
FN, Mayer KH, Para MF. Placebo-controlled
phase 3 trial of a recombinant glycoprotein
120 vaccine to prevent HIV-1 infection. J In­
fect Dis 2005;191:654-65.
2. Pitisuttithum P, Gilbert P, Gurwith M, et al.
Randomized, double-blind, placebo-con­
trolled efficacy trial of a bivalent recombi­
nant glycoprotein 120 HIV-1 vaccine among
injection drug users in Bangkok, Thailand.
J Infect Dis 2006;194:1661-71.
3. Buchbinder SP, Mehrotra DV, Duerr A, et
al. Efficacy assessment of a cell-mediated
immunity HIV-1 vaccine (the Step Study):
a double-blind, randomised, placebo-con­
trolled, test-of-concept trial. Lancet 2008;372:
1881-93.
4. Rerks-Ngarm S, Pitisuttithum P, Nita­
yaphan S, et al. Vaccination with ALVAC and
AIDSVAX to prevent HIV-1 infection in
Thailand. N Engl J Med 2009;361:2209-20.
5. Haynes BF, Gilbert PB, McElrath MJ, et al.
Immune-correlates analysis of an HIV-1 vac­
cine efficacy trial. N Engl J Med 2012;366:
1275-86.
DOI: 10.1056/NEJMp1312711
Copyright © 2013 Massachusetts Medical Society.
Medicare’s Physician Value-Based Payment Modifier —
Will the Tectonic Shift Create Waves?
Alyna T. Chien, M.D., and Meredith B. Rosenthal, Ph.D.
F
or at least two decades, the
Centers for Medicare and
Medicaid Services (CMS) has been
transforming itself from a passive payer to an active purchaser
of health care, a process that was
accelerated by the passage of the
2010 Affordable Care Act (ACA).
One ACA provision ushered in a
new payment paradigm for physicians — the Physician ValueBased Payment Modifier (PVBM).1
The PVBM seeks to financially
reward physicians who provide
health care that is high value —
both high in quality and low in
cost.2 Although the PVBM is being rolled out to physicians in
large groups first, the legislation
requires that the PVBM be applied
to all physicians and groups by
January 1, 2017.1
The PVBM reward formula is
a simple, relative system in which
performance is assessed in two
dimensions (quality and cost),
with payments accruing to physicians who have above-average
performance along both dimensions. Physicians who perform
worse than average or choose not
to be involved will be paid less;
physicians with average performance will experience no change.
The maximum bonus is about 2%
2076
of Medicare fees, and the maximum penalty is approximately 1%.
For CMS, scoring physicians relative to one another achieves budget neutrality. For physicians, it
eliminates the effects of common
shocks to performance, such as
an influenza epidemic or vaccine
shortage. The key disadvantage
of this incentive structure is the
inherent uncertainty for physicians
about the amount of improvement
that will be necessary to receive
a bonus or avoid a penalty.
Although the PVBM will eventually affect all the approximately
600,000 physicians who currently
bill Medicare, the program will
first target the 180,000 physicians
working in practices of 100 or
more eligible professionals and
then expand to include the 220,000
physicians working in practices
of 10 or more. This first group of
physicians has now declared
whether they will participate in
the PVBM or accept de facto penalties. Will this tectonic shift in
CMS’s approach to physician payment set off a new wave of efforts to improve quality and cost
performance?
Examination of CMS’s path
leading up to the PVBM, as compared with the parallel Hospital
Value-Based Purchasing (HVBP)
program, offers some insight into
the answer to this question (see
timeline). In particular, the timeline highlights gaps in physicians’
preparedness for value-based purchasing relative to that of hospitals. Three major CMS programs
have served as building blocks
for HVBP: a quality-reporting program known as Hospital Inpatient Quality Reporting; Hospital
Compare, which allows the public to view quality information;
and a direct test of pay for performance in hospitals under the
Premier Hospital Quality Incentive Demonstration (Premier).
In terms of active involvement
in quality measurement, CMS had
achieved and maintained participation levels of over 90% among
the roughly 3500 hospitals participating in the Hospital Inpatient
Quality Reporting program for
9 years preceding the start of HVBP.
By comparison, after 6 years, only
one third of physicians participate in the comparable Physician
Quality Reporting System. Whereas the Hospital Compare website
had been presenting information
on hospital quality for 9 years
before the beginning of HVBP,
CMS is not scheduled to debut
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