an antigen that stimulates an appropriate germline immunoglobulin gene and then boost with a
series of immunogens recapitulating the evolution of the virus as it escapes from Ab-mediated
immune pressure, thus steering B cell differentiation through mutational steps that are required
in vivo for the production of bnAbs. Targeting of
more than one epitope will likely be needed,
given the mutation rate of HIV. Notably, there
are currently no data demonstrating that this
approach is feasible.
Simultaneously, there is a growing literature
describing rationally designed vaccines that induce protective conventional Abs. This approach
depends on identification of the epitopes recognized
by protective conventional monoclonal Abs (mAbs)
and the subsequent use of structural, bioinformatics, and molecular methods to design immunogens that will induce polyclonal Abs similar to
the originally identified protective mAbs. This
approach has led to the design of vaccine candidates against several pathogens (17, 18), and
epitope-scaffold immunogens have already been
shown to successfully induce conventional cross-clade neutralizing Abs against HIV (19–21). Initially, conventional Abs were shown to be protective
against HIV by demonstrating that chimpanzees
could be protected by infusing the challenged
animals with immunoglobulin G (IgG) from an
HIV-infected chimpanzee (22). Subsequently, human mAbs, representing conventional Abs made
by most chronically infected individuals, were
shown to neutralize multiple lab-adapted and/or
primary isolates in vitro (23–29), and two of these
mAbs, specific for the third variable region (V3)
of the HIV gp120 envelope glycoprotein, provided
protection against heterologous HIV strains in
relevant animal models (30, 31). More than 90%
of chronically infected HIV+ subjects make similar V3 Abs (32).
Unlike in many viral infections, HIV-infected
individuals can become “superinfected” with a
second HIV strain. This might suggest that Abs
that develop in HIV patients are not protective.
However, several studies suggest that Abs made
in HIV-infected individuals do affect the rate of
superinfection. For instance, superinfected individuals had lower levels of cross-protective and
autologous neutralizing Abs than the nonsuper-infected case-controls (33, 34). Although some
studies are contradictory to these (35, 36), and
other data suggest that cytotoxic T lymphocytes
are capable of imposing selective pressure on
HIV (37), results from a recent adequately powered
study demonstrated that a first HIV infection reduces the risk of a subsequent infection by ~50%
in high-risk Kenyan women (38). Additional evidence for the protective role of Abs comes from
studies of maternal-fetal transmission. Although
not replicated universally, several studies showed
lower transmission rates from infected pregnant
women with high Ab titers or with high-affinity/
avidity Abs to portions of the HIV-1 envelope
These studies complement those showing that
Abs commonly exert strong and rapid immune
pressure on viruses in vivo. For instance, when
serial plasma samples from patients with primary
HIV infection were examined for neutralizing
activity against autologous viruses, the plasma
virus continually and rapidly evolved to escape
neutralization (40, 41). Moreover, as early as 2
weeks after seroconversion, very low titers of
neutralizing Abs select for escape viruses in
acutely infected patients (42). These studies in-
dicate that Abs produced in the majority of pa-
tients can eliminate viruses bearing cognate
antigenic determinants. If a vaccine were to
produce a similar conventional polyclonal Ab
response in uninfected individuals, it may be
possible that most or all of an incoming virus
inoculum could be eliminated by these Abs.
Additional support for the role of Abs in pro-
tection comes from the RV144 clinical vaccine
trial in which subjects received four doses of a
recombinant HIV–avian pox virus and two doses
of gp120 proteins from two different HIV sub-
types. An estimated vaccine efficacy of 31% was
noted at 3 years of follow-up (43) and 60% at
1 year after immunization (44). Higher levels of
IgG Abs specific for epitopes in the second variable
loop (V2) and V3 region of gp120—Abs commonly
found in HIV-infected individuals (32, 45, 46)—
were significantly associated with the reduced
rate of infection (47–49). Several independent
studies have confirmed that Abs to V2 and V3
correlated with the reduced rate of infection noted
in RV144 vaccine recipients (48, 50–52).
There are, therefore, many lines of evidence
that indicate that despite their reduced potency
and breadth as compared to bnAbs, conventional
Abs made by the majority of HIV-infected indi-
viduals may be able to prevent infection. More-
over, conventional Abs display additive and
synergistic activity (53–56) that may explain the
ability of polyclonal conventional Ab responses
to reduce the risk of HIV-1 infection.
At this point, there are no definitive data dem-
onstrating that either vaccine-induced conven-
tional or exceptional Abs will result in protection
from HIV infection in humans. The clearest in-
dication comes from the data emanating from
the RV144 vaccine trial (47, 48, 50–52), but, strong
as these data are, there is as yet no absolute proof
of the hypothesis that conventional Abs are pro-
tective in humans. Nor do such data exist for
bnAbs. In addition, it is possible that vaccine-
induced conventional Abs will need to be induced
at higher titers than bnAbs and may not protect
against as many strains. The data do suggest that
conventional Abs may be more feasible to induce,
whereas bnAbs may ultimately be more effective.
Therefore, both approaches have their strengths
and weaknesses, and both must be pursued with
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This work was sponsored by funds from the Department of
Veterans Affairs, Veterans Health Administration, Office of
Research and Development, and grants from the National
Institutes of Health (P01 AI 100151 and R01 HL59725).
27 May 2014; accepted 18 June 2014