Indian J Med Res 121, April 2005, pp 568-581
568
In June 1981, the Center for Disease Control
(CDC) in the United States reported the first clinical
evidence of a disease that would become known as
Acquired Immunodeficiency Syndrome (AIDS).
Twenty-three years later, the AIDS epidemic has
spread all over the world. Since the beginning of the
epidemic, 63 million people have been infected with
HIV. Globally, over 38 million people are today living
with HIV infection, with 5 million new infections
acquired annually, and 14,000 daily1. Over 95 per cent
of new HIV infections occur in developing countries,
mainly in Sub-Saharan Africa and South-East Asia.
There is an urgent need to explore all possible
approaches to control the epidemic, in particular,
preventive measures such as health education, condom
use, safe sex practices, and treatment of sexually
transmitted diseases, preventive vaccines and topical
microbicides. If considerable progress has been made
in treatment with antiretroviral drugs and their large-
scale implementation, the need for an AIDS vaccine
has spurred an unprecedented effort of research and
development worldwide, especially in South-East
Asia2. Preventive vaccines represent our only long-
term hope to stop the epidemic3.
Since the first report of HIV infection among sex
workers in Chennai in 19864, it is estimated that over
5.1 million people were infected with HIV in India by
the end of 2003, representing a high public health
burden. HIV infection has spread to all the states in
AIDS vaccine development: Perspectives, challenges & hopes
Jean-Louis Excler
International AIDS Vaccine Initiative, India, New Delhi, India
Accepted January 28, 2005
The worldwide quest for an AIDS vaccine represents an unprecedented scientific and human
challenge for the 21st century. Preventive vaccines represent our only long-term hope to stop
the epidemic. AIDS vaccines must be seen as the ultimate prevention tool that will complement
the existing prevention strategies in place. The acceleration of vaccine development through the
parallel exploration of several scientific approaches and implementation of clinical trials are
the best and probably only way to reach this goal, and the best vaccines have moved into phase
II and efficacy trials. Ideally an AIDS vaccine should induce both neutralizing antibodies against
HIV-1 primary isolates and cell-mediated responses. AIDS vaccines could prevent either HIV
infection or progression to disease and decrease transmission by reducing the HIV viral load.
Most of the vaccine approaches developed so far aim at inducing cell-mediated immune responses.
New vector-based vaccines include modified vaccinia Ankara, adeno-associated virus, adenovirus
and alpha viruses. Considerable efforts are on to develop vaccines that would induce neutralizing
antibodies. All vaccines tested so far in humans have proven to be safe. This long-term endeavour
requires strong and renewed political leadership and commitment, flexibility of processes, medical
and scientific dedication and collaboration on a mission mode along with community participation
for immediate action. Recent developments in India highlight clearly the commitment of the
Government of India and the scientific community to a long-term global effort to develop an
AIDS vaccine.
569
India and high prevalence rates have been reported
from Maharashtra, Karnataka, Tamil Nadu, Andhra
Pradesh, Manipur, and Nagaland. A majority of HIV
infections are due to sexual transmission  followed by
intravenous drug use and mother-to-child
transmission5. The HIV epidemic has been spreading
from high risk to low risk populations and from urban
to rural areas during the last 12-13 yr6-9. The need to
develop an HIV vaccine in India has become
particularly pressing.
Scientific and strategic challenges
The main scientific obstacles to the development
of an AIDS vaccine are summarized in Table I.
The high error rate of the viral reverse transcriptase
leads to continuous mutations in the HIV genome.
HIV-1 is characterised by its genetic diversity and
hypervariability, especially in the envelope domain,
to a lesser extent in core and regulatory genes. In
addition, the genetic sequence of the full genome has
allowed determining recombination between subtypes,
now well established10-12. In Asia, the HIV group M
subtype A/E (E envelope, A gag/pol) is predominant
(>75%) in Thailand13  and Myanmar, followed by
subtype B (close to the North American and European
B), essentially found in injecting drug users (IDUs),
and subtype C in northern Thailand. In Indonesia,
subtypes B (predominant) and E are both circulating14.
In China, the presence of subtypes B and C among
injection drug using populations in southern Yunnan
Province yielded CRF07_BC and CRF08_BC which
subsequently became the predominant viruses as the
HIV-1 epidemic spread to the north and the east15-18.
In India HIV-1 subtype C is predominant (91%)
(subtype C accounts for 47.2% of all HIV infections
worldwide19, followed by subtypes B, A and E20-25.
Recombinants (A/C, B’/C) have also now been
described in India26. HIV-2 is also circulating. This
may have tremendous implications for the design of
HIV vaccines. A vaccine protecting against a subtype
may not be protective or only partially protective
against another subtype or recombinant.
The immune correlates of protection are still
unknown27. Both arms of the immune system
(humoral and cell-mediated) are thought however to
be important elements for protection. The best
vaccine approach would prevent the establishment
of HIV infection of the host upon exposure. A typical
immune response to HIV infection involves the
development of both neutralizing antibodies and cell-
mediated immune responses. However, despite these
immune responses, the persistence of HIV-1 reflects
its ability to evade elimination by the immune system
and to replicate predominantly in antigen-presenting
and regulatory immune cells, enabling continuous virus
replenishment. Efforts aim at developing vaccines that
would induce both neutralizing antibodies and
cytotoxic T lymphocytes (CTL) against CCR5
primary HIV isolates 28 . The humoral arm produces
virus-neutralizing antibodies that, when fully effective,
completely prevent virions from infecting new host
cells. Essential structural components of the
glycoproteins required for host-cell interaction and
entry are rendered inaccessible to antibody, and the
remainder of the molecule is “hidden” from antibody
assault. The complex interactions between the
envelope and its receptors (CD4 and chemokines
receptors), the partial protection from antibody by
glycosylation of the envelope-chemokine receptor and
stearic hindrance make the envelope a remarkable
functional molecule that is appropriately exposed to
the environment of the host cell surface but can also
thwart effective antibody interaction. Several
monoclonal antibodies have been described as
“broadly” neutralizing against diverse HIV-1 isolates.
However, the breadth and potency of their activity
remains limited29. Though the mechanisms that lead
to neutralizing antibodies are relatively well
Table I. Scientific obstacles to the development of
AIDS vaccines
Antigenic diversity and hypervariability of the virus
Transmission of disease by mucosal route
Transmission of the virus by infected cells
Resistance of wild type virus to seroneutralization
Integration of the virus genome into the host cell chromosomes
Latency of the virus in resting memory T-cells
Rapid emergence of viral escape mutants in the host
Downregulation of major histocompatibility (MHC)
class I antigens
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570 INDIAN J MED RES, APRIL  2005
understood, scientists are still unable to make relevant
immunogens capable of inducing such antibodies. An
International Neutralizing Antibody Consortium has
been set up and is co-ordinated and co-funded by
International AIDS Vaccine Initiative.
The antiviral cellular immune response plays a
crucial role in controlling virus replication, especially
when effective during the phase of acute infection30,31.
The objective of a vaccine that elicits specific cellular
immunity is to greatly enhance the pool of anti–HIV-
1 CD4 memory and CD8 CTLs in the uninfected
person. These established memory cells will then be
capable of rapidly proliferating upon initial virus
infection. The immediate proliferation of effector
CTLs will, in theory, result in an interaction between
the virus and the immune system whose dynamics
favour the immune response, yielding a rapid
clearance of infection and a lower persistent viral
load. Such a vaccine will likely not prevent new HIV
infection, but it should have both beneficial individual
and epidemiological consequences32. Encouragingly,
the ability of the virus to fully “escape” from the
cellular immune response through mutation may be
limited by functional constraints on virus structure33,34.
The vaccine strategies currently developed focus on
the development of a cell-mediated immune response,
essentially through HIV-specific CD8 cytotoxicity.
However, the relevance CD8 T-cell measurements
currently used in animal studies and clinical trials such
as ELISpot INF?  have been questioned. If the ELISpot
INF?  still represents the yardstick of measurement of
CTL activity, such measurement is thought to give a
partial image of the true immune responses susceptible
to protect against HIV. There is a growing consensus
that other parameters should be looked at, including
the CD8 memory by measurement of IL2 production,
the secretion of granzyme B and perforin as preferable
markers of the CTL activity35. However, such assays
need to be standardized and validated.
The elicitation of cellular immunity by a vaccine
requires that vaccine vectors be developed that can
“deliver” genes encoding the target viral immunogens
to immune system antigen-presenting cells. A number
of such vectors are currently being developed and
tested in preclinical and early phase clinical trials.
The more promising technologies include various
replication defective viruses and so-called “naked”
DNA vectors used in multiple combinations. However,
to date, individual vector systems have exhibited
various deficiencies such as poor potency and negative
effects of pre-existing antivector immunity36.
Relevant animal models are lacking. In non-human
primate models, these vaccines have elicited immune
responses that range from highly to poorly effective
in their ability to mitigate infection after challenge
with the virus37. The validity of animal models for
protection will be resolved only when comparison of
these animal results with the results of “proof of
concept” (or phase IIb) and efficacy trials in humans
are made possible.
Since most of HIV transmission occurs through
sexual transmission, the development of an AIDS
vaccine that would elicit protective immunity at the
mucosal level has received special attention. The
conduct of animal studies and clinical trials raised
however methodological issues such as the need to
harmonize and validate the methods of sample
collection as well as of the measurement of immune
responses at the mucosal level. The current cell-
mediated immunity-oriented vaccine strategies may
not be adapted to the situation since there seems to be
a poor correlation between HIV shedding in semen
and the systemic CD8 CTL response in humans38.
Programmatic challenges
The implementation of AIDS vaccine development
programmes encounters several difficulties (Table II).
The implementation and conduct of HIV vaccine
clinical trials are difficult, long and costly. Recruitment
Table II. Programmatic difficulties to the development of
AIDS vaccines
Insufficient political leadership
Insufficient fundings allocated to AIDS vaccines
Lack or insufficient coordinated approach
Regulatory authorities in developing countries
Slow approval process
Standardization of assays and reagents
Length of clinical trials, especially of efficacy trials
571
Table III. Clinical trials in developing countries
Year Country Phase Product No. of
volunteers
1993 China II V3 branched peptide 23
1994 Thailand II V3 branched peptide 30
Brazil II V3 branched peptide 30
1995 Thailand I/II rgp 120 B (MN) 30
I/II rgp 120 B (SF2) 54
1996 Cuba I V3-multi-epitope peptide 30
1997 Thailand II rgp 120 BE (SF2/CM235) 380
1998 Thailand II rgp 120 BE (MN/A244) 92
1999 Uganda II ALVAC vcp205 40
Thailand III rgp 120 BE (MN/A244) 2,545
2000 Thailand I/II ALVAC vCP1521 + rgp 120 BE 60
I/II ALVAC vCP1521 + rgp 160 E 70
I/II ALVAC vCP1521 + rgp 120 BE 125
2001 Kenya I DNA-HIVA 18
Haiti II ALVAC vCP1452 + rgp120 BB 40
Trinidad II ALVAC vCP1452 + rgp 120 BB 40
Brazil II ALVAC vCP1452 + rgp 120 BB 40
2002 Perú II ALVAC vCP1452 + rgp 120 BB 40
Kenya I MVA-HIVA 18
2003 Uganda II DNA-HIVA + MVA-HIVA 50
Botswana I DNA-multi-epitope 12
Kenya II DNA-HIVA + MVA-HIVA 120
South Africa II MVA-HIVA 55
I VEE-vectored C gag 40
South Africa & I/II MRKAd-5 gag B
Malawi MRKAd-5 gag 87
Brazil & Peru I/II MRKAd-5 gag B 87
Thailand I/II MRKAd-5 gag B 87
Haiti & Puerto Rico I/II MRKAd-5 gag B 87
Thailand III ALVAC vCP1521 + rgp 120 BE 16,000
2004 USA, Later: Canada, Peru IIb MRKAd-5 gag/pol/nef B 1,500
Dominican Republic, Haiti,
Puerto Rico, Australia
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572 INDIAN J MED RES, APRIL  2005
of lower-risk volunteers for phases I trials, and of at-
risk volunteers for phase II and III efficacy trials is
rendered more difficult in less-educated populations
exposed to stigma and discrimination, rumours and
misunderstandings, and media opinion. Safeguarding
the rights and welfare of individuals participating as
research subjects in developing countries is a priority.
In September 1997 the Joint United Nations
Programme on HIV/AIDS (UNAIDS) embarked on
a process of international consultation; its purpose
was further to define the important ethical issues and
to formulate guidance that might facilitate the ethical
design and conduct of HIV vaccine trials in
international contexts39,40.
The difficulties of implementing HIV vaccine
efficacy trials in developing countries have been
reviewed elsewhere41,42. HIV incidence rates although
still high in some high-risk groups such as discordant
couples43  or intravenous drug users44 and commercial
sex worker groups45, show a general trend to
decreasing. This is mainly due to the implementation
of aggressive intervention programmes of prevention
and treatment in these groups over the past 10 yr. As
a consequence of lower incidence rates, vaccine
efficacy trials will need to be multi-centric and/or
multi-country in order to reach the number of
participants needed at analysis for a given mode of
transmission.
Over the past 10 yr, several developing countries
have joined the international effort of AIDS vaccine
development (Table III). The implementation of
clinical trials in developing countries raised new
challenges regarding the approval process and
regulatory issues. In several instances, the approval
process was poorly defined, ethics committees and
regulatory authorities unprepared and inadequately
staffed for reviewing complex dossiers of “high tech”
genetically engineered products and dealing with “last
minute” changes that characterizes research and
development. This situation leads most of the time to
lengthy approval process and delays in trial initiation.
Although considerable efforts have been made in
strengthening the capacity of ethics committees and
regulatory agencies in developing countries, more
remains to be done to shorten delays to trial initiation.
AIDS vaccine approaches
Since 1987, when the first preventive HIV vaccine
candidate entered clinical trials, more than 40 vaccine
candidates have been evaluated in safety and
immunogenicity trials, and one candidate has
progressed to efficacy trials. More than 10,000 HIV-
uninfected volunteers have participated in clinical
trials of HIV vaccines between 1987-2003. Databases
of AIDS vaccines in human trials have now been
established by the International AIDS Vaccine
Initiative (IAVI) (www.iavi.org) and US National
Institutes of Health Vaccine Research Center
(www.vrc.nih.gov), and provide details and references
for the individual trials. Several vaccine concepts,
schedules of immunization, routes of administration,
and adjuvants have been tested46. Classical vaccine
strategies based on live-attenuated or whole-
inactivated HIV have severe limitations47,48. Most
efforts to develop an AIDS vaccine have therefore
focused on newer vaccine approaches.
Recombinant envelope subunits: Recombinant soluble
HIV and Simian immunodeficiency virus (SIV)
glycoproteins have been used as subunit vaccines.
HIV-1 gp160, gp140, or gp120 induced only a
transient response in primates even with strong
adjuvants or special delivery formulations. They did
not protect macaques from challenge with the virulent
SIVmac. These studies have underlined the importance
of the conformational integrity of the envelope
glycoprotein for the induction of neutralizing
antibodies: current envelope vaccine candidates elicit
high gp120-binding antibody titres with neutralizing
activity against matched tissue culture laboratory-
adapted virus strains but not primary HIV-1 isolates.
The antibodies induced by gp120 are usually incapable
of neutralizing primary CCR5 isolates, even though
they can neutralize the homologous CXCR4 virus
strain. They can therefore prevent infection if animals
are challenged with a homologous CXCR4 virus but
not with a CCR5 virus strain. Efficacy trials with
monomeric gp120 derived from circulating primary
isolates have demonstrated their absence of efficacy
against HIV infection in humans49.
Several approaches have been undertaken to
overcome these obstacles including mixing gp120
573
from primary isolates, and soluble gp140 glycoprotein
trimers. The resulting molecules showed enhanced
immunogenic potency, but the improvement was far
from optimal. The removal of glycosyl moieties to
unmask neutralization epitopes, the making of gp120-
CD4 receptor complexes or the deletion of the 1st
and 2nd variable loops from gp120 (currently tested
in human volunteers) have been used as immunogens
and shown to induce broadly neutralizing antibodies50.
The HIV-1 Tat protein is more conserved than
envelope proteins, is essential in the virus life cycle
and is expressed very early upon virus entry. In
addition, both humoral and cellular responses to Tat
have been reported to correlate with a delayed
progression to disease in both humans and monkeys.
This suggested that Tat is an optimal target for vaccine
development aimed at controlling virus replication and
blocking disease onset. Subunit vaccines based on
the accessory protein Tat have been developed and
have demonstrated at least partial protective efficacy
in HIV envelope and SIV core genes chimeric
construct or SHIV macaque models and are currently
tested in humans51. Gp120 nef/tat fusion adjuvanted
subunit protein vaccine induces mediocre immune
responses in humans measured by ELISpot INF? 52 .
Synthetic peptides: Synthetic peptide immunogens
either linear or branched initially concentrated on the
V3 loop of gp120. Well-tolerated, they were unable to
induce neutralizing antibodies against primary
isolates53,54.
Although peptides and proteins usually do not
induce a class I–restricted CD8 response  in vivo,
lipopeptides have such a capacity and may represent
an interesting formulation for inducing or boosting the
CTL immune response to HIV. Indeed, long
lipopeptides with a fatty acid tail can induce broad
cellular immune reponses in humans as well as in
animals. Lipopeptides tested in France gave impressing
immune responses measured by ELISpots INF?  with
up to 83 per cent of HIV-specific CD8 responders.
The lipopeptides with a monolipid tail and a tetanus
toxoid peptide appeared to be superior to double lipid
tail peptides55-57.
Live recombinant vectors: Live recombinant vector
vaccines are either a live attenuated viral or bacterial
strain used as a vector to carry HIV genes encoding
the antigens of interest (Table IV). They are able to
stimulate both humoral and cell-mediated immunity.
Table IV. Live recombinant vectors used as HIV-1 vaccines
Viruses Bacteria
Pox viruses: vaccinia, canarypox (ALVAC), fowlpox, Bacillus Calmette & Guérin
Modified Vaccinia Ankara (MVA), NYVAC Salmonella
Adenoviruses Shigella
Adeno-associated viruses (AAV) Lactobacillus
Alphaviruses: Venezuelan equine encephalitis, Sindbis, and Streptococcus
Semliki Forest (SFV) viruses Listeria
Flaviviruses: Yellow fever virus 
Rhabdoviruses: vesicular stomatitis and rabies viruses
Myxovirus: Influenza virus
Paramyxoviruses: Sendaï virus, measles virus
Picornavirus: poliovirus
NYVAC, Attenuated vaccinia by genetic engineering
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574 INDIAN J MED RES, APRIL  2005
Pox vectors such as vaccinia virus vectors were
the first to be tested in animals and humans. They
induce HIV-specific CTL responses but weak and
transient anti-HIV antibody responses and can confer
protection in macaque models.
The lack of safety of vaccinia virus recombinants
in immunocompromised people has led to prefer the
use of attenuated vaccinia virus strains such as
NYVAC or the Modified Vaccinia virus Ankara
(MVA), a highly attenuated, host range–restricted
strain of vaccinia virus. NYVAC HIV-1 subtype C
(an attenuated slow replicative genetically engineered
vaccinia) was recently tested in humans. A maximum
of 50 per cent ELISpot INF ?  response was
observed58 .
In non-human primates, MVA recombinants were
found to induce potent CTL responses able to partially
control virus loads after challenge with pathogenic
SHIV or SIV59. A new MVA vector was engineered
that is genetically blocked for progression through the
poxvirus replication cycle via the deletion of the uracil-
DNA glycosylase (udg-) gene. Macaques immunized
with this MVA udg- exhibited significantly higher
levels of CD8 and CD4 T-cell proliferation one week
post-immunization compared to normal MVA vector.
In prime-boost experiments, measles vector prime
and MVA udg- boost induced stronger responses than
measles or MVA udg- alone60.
Other pox vectors, non-replicative in mammalian
cells, have been developed including canarypox
(ALVAC) or folwpox viruses. Although very safe in
humans, since non-replicative, they are less
immunogenic than vaccinia. Results from several
Phase I and II trials with recombinant canarypox
vectors have demonstrated the induction of CD8 CTL
in a limited proportion of vaccinees (15-30%) at any
given time point post-immunization. Interestingly,
some CTL responses generated by recombinant
canarypox vectors were cross-clade61.
Human adenovirus types 4, 5, and 7 can be
administered orally or intranasally and can induce both
systemic and mucosal immunity. Recently, an Ad5
recombinant expressing HIV-1 Gag was found to
successfully induce cellular immune responses in
rhesus macaques and to attenuate infection and
mitigate disease progression after challenge with a
pathogenic SHIV. Recently DNA priming and
recombinant Ad5 boosting was able to induce strong
cell-mediated immune responses in human volunteers.
The priming effect of DNA was however limited.
Adeno 5 subtype B was tested in human volunteers62.
DNA prime does not bring substantial advantage over
Ad5 alone, especially in Ad5 naïve subjects.
Volunteers without pre-existing immunity to Ad5
develop strong ELISpot responses in up to 82 per cent
of them. In contrast, the percentage of responders is
inversely proportional to the titres of pre-existing Ad5
antibody titer (down to 28%). In developed countries
the percentage of Ad5 immune individuals is about
30 per cent with low titers increasing to 70 per cent
with high titres in developing countries63.
Defective alphavirus “replicons” such as
Venezuelan Equine Encephalitis (VEE) virus, Sindbis
virus and Semliki Forest virus (SFV) replicons offer
the advantages of an important amplification of the
viral message after infection and are able to target
Table V. Prime-boost strategies tested in animals or humans
Vaccinia + recombinant envelope subunit
Canarypox + recombinant envelope subunit or synthetic
lipopeptide
Salmonella + recombinant envelope subunit
Recombinant envelope subunit + synthetic peptide
DNA + recombinant envelope subunit
DNA + pox virus (canarypox, fowlpox, MVA, NYVAC)
DNA + adenovirus
Vector + vector
homo- or heterologous adenovirus
adenovirus + canarypox
AAV + homo- or heterologous AAV or MVA
MVA + fowlpox
SFV + MVA
MVA, Modified vaccinia Ankara, AAV, Adeno-associated virus,
SFV, semliki forest virus; NYVAC, Attenuated vaccinia by
genetic engineering
575
dendritic cells, resulting in efficacious antigen
presentation64.
AAV is a naturally occurring virus that depends on a
helper virus for replication.  Although pre-existing
immunity to AAV is common in the US and Europe,
extensive epidemiological studies have found this virus
to be non-pathogenic. The AAV-based vaccine is not
capable of replication as it lacks the requisite AAV
viral elements that respond to helper adenovirus co-
infection and the vaccine is thus incapable of
replication, even in the presence of helper viruses.
Persistence of vaccine DNA sequences in cells occurs
by a mechanism involving an unintegrated episomal
concatamer65. Although 25-60 per cent of humans in
the US and Europe have binding antibodies against
AAV, only a small percentage of the population exhibit
neutralizing antibody, and the low titres observed
likely will not prevent a ‘vaccine take’. No data on
pre-existing immunity to AAV is available for
Southeast Asia and Africa. Preclinical data show that
AAV-based vaccines induce both antibody and T-cell
responses against the inserted genes when delivered
as a single intramuscular injection. Immune responses
in mice and macaques persist at least six months after
a single intramuscular injection. AAV-based AIDS
vaccine clinical trials have been initiated in Europe.
Numerous other virus vector systems like the
attenuated vaccine strains of measles or yellow fever
viruses, poliovirus replicons, rabies virus, vesicular
stomatis virus, or Sendaï virus are being developed for
the preparation of live recombinant HIV vaccines (Table
IV). Live recombinant bacterial vaccines have also been
developed including bacillus Calmette-Guerin (BCG),
Salmonella,  Listeria monocytogenes and Shigella66.
However, in individuals previously exposed to the
vector and who developed a residual immunity to the
vector, most live recombinant viral or bacterial vectors
show a decreased immunogenicity compared to naïve
hosts. Volunteers with low pre-existing Ad5 antibody
titres developed strong cell-mediated immune
responses but not those with high pre-existing
immunity67. This serious limitation is not observed with
canarypox or fowlpox vectors but applies to BCG,
poliovirus, or human adenovirus. It also applies to
MVA and NYVAC in the populations vaccinated
against smallpox. This might also be an issue for
booster injections, as successive immunizations with
the same vector will induce immunity to the vector.
Naked DNA: Injection into the muscle or the epidermis
of a purified plasmid DNA that carries a gene
encoding an antigen under the control of an
appropriate mammalian transcription promoter leads
to expression of the antigen in situ and triggers an
immune response, mostly of the Th1 type. DNA
vaccines alone even when engineered as synthetic
HIV-1 genes with optimized codons or formulated
with cytokines or various delivery systems have
however been disappointing, inducing weak immune
reponses in primates and humans68.
Prime-boost concept: In animals, priming with a viral
vector or nucleic acid vaccine, followed by boosting
with either another vector or subunit/peptide vaccine,
induced stronger immune responses compared to
vaccination with either vaccine alone 69. Several
prime-boost strategies have been tested over the past
decade. They are summarized in Table V.
Prime-boost combinations using a DNA vaccine
for priming and recombinant MVA or fowlpox virus
vaccines for boosting elicited the best CTL responses
in macaques70  that showed  lower virus loads and
prolonged survival following pathogenic SHIV
challenge71. Recombinant vaccinia, MVA, and fowlpox
constructs were comparable in their immunogenicity.
Moreover, whereas the magnitude of the peak
vaccine-elicited T lymphocyte responses in the
recombinant pox virus-boosted monkeys was
substantially greater than that seen in the monkeys
immunized with plasmid DNA alone, the magnitude
of the CTL responses decayed rapidly and was
comparable to those of the DNA-alone-vaccinated
monkeys by the time of viral challenge. Consistent
with these comparable memory T-cell responses, the
clinical protection seen in all groups of experimentally
vaccinated monkeys was similar. This study, therefore,
indicates that the steady-state memory, rather than
the peak effector vaccine-elicited T lymphocyte
responses, may be the critical immune correlate of
protection for a CTL-based HIV vaccine72. Recently,
a prime-boost regimen with DNA + MVA expressing
strings of CTL epitopes from HIV-1 subtype A was
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576 INDIAN J MED RES, APRIL  2005
tested in human volunteers in United Kingdom, Kenya
and Uganda and showed disappointing results. Less
than 20 per cent of vaccinees developed ELISpot
INF?  responses73,74. Whether different MVA
constructs will add significant benefit remain to be
demonstrated.
A prime-boost regimen using DNA prime and
fowlpox (FPV) boost was tested in macaques
subsequently SHIV-challenged. Interestingly, priming
with two DNA injections followed by one FPV booster
injection was equivalent to three DNA injections only
as measured by decrease in viral load after challenge
although the first regimen induces stronger ELISpot
INF?  responses. This may suggest that ELISpot IFN?
may not be a good immune correlate of protection.
In Australian volunteers, the low (1.5 mg) and high
(4.5 mg) doses of DNA vaccine induced similar
immune responses75.
Prime-boost with lipopeptides and canarypox did
not show improvement in immune responses over
lipopeptides alone. Lymphoproliferation following
peptides was detected in all vaccinees and in only 38
per cent with canarypox alone76.
Ad5 prime followed by ALVAC (canarypox) boost
induces a synergistic response in animals77, which was
unfortunately not observed in humans.
In order to circumvent the pre-existing immunity
issue to the vaccine vector, efforts now focus on
developing vaccines derived from adenovirus
subtypes rarely infecting humans such as Ad11 and
Ad35. Ad11 prime boosted either by Ad5, Ad35 or
Ad11 shows that heterologous is superior to
homologous boost (Ad11+Ad35)78.
In animals, AAV subtype 1 seems to induce
stronger immune response measured by ELISpot INF?
as compared to AAV subtype 2. Several prime-boost
regimens using homologous or heterologous AAV
constructs and MVA were compared in macaques:
AAV2+AAV1>AAV2+AAV2>AAV2+MVA>MVA+MVA.
When using recombinant vectors, heterologous prime-
boost strategies seem to induce stronger cell-mediated
immune responses than homologous ones79.
Pediatric trials: The rapidly increasing prevalence of
mother-to-child transmission (MTCT) of HIV-1
worldwide has resulted in an urgent need for effective
preventive strategies80. Although antiretroviral regimens
have shown considerable efficacy in reducing vertical
transmission of HIV, it is still not known whether such
regimens would prevent the transmission of HIV-1
through breastfeeding beyond the neonatal period81. In
addition, children who escape MTCT are again at risk
for infection when they become sexually active as
adolescents. An infant vaccine regimen, begun at birth,
represents an attractive immunization strategy and might
also provide the basis for lifetime protection against HIV-
1 infection. However, the development of protective
immunity may take time and passive coverage until
immunization is complete would be important in
preventing breast milk transmission of HIV-1. Since the
majority of infants acquire infection at or within 6 months
of birth, efficacy data could be available as early as 6
months - 1 yr following the initiation of the Phase III trial.
Adolescents: It is acknowledged that adolescents
should benefit in priority of a safe and efficacious
AIDS vaccine once available before they enter into
their sexual life. The participation of adolescents in
efficacy trials raises several ethical and legal concerns
and is thought to be unnecessary for licensure at least
in the general population. The debate however
remains open for some high-risk groups such as sex
workers and men having sex with men that de facto
include some adolescents. The growing consensus is
that once efficacy is demonstrated in adults, bridging
studies should be conducted in adolescents82.
Role of India: The last two years have been for the
Government of India through leading institutions
including the Indian Council of Medical Research
(ICMR), the National AIDS Control Organisation
(NACO) and their partner International AIDS Vaccine
Initiative (IAVI), a period of intense activities and
great achievements in the domain of AIDS vaccine
development. Other institutions under the Department
of Biotechnology (DBT) leadership are also actively
involved in several vaccine approaches.
In 2002, a multiple AIDS vaccine candidate
strategy approach was adopted. This strategy would
allow to speed up the testing of several vaccines in
577
parallel rather than sequentially to ensure that an
effective vaccine is available at the earliest. As a
consequence, it was decided to set up centres of
excellence for AIDS vaccine clinical and laboratory
evaluation at two ICMR Institutes in India. This
strategy would contribute significantly to the research
and development capacity building in India.
One centre is located at the National AIDS
Research Institute (NARI), Pune, working towards
conducting the first phase I clinical trial with the AAV-
based AIDS vaccine in 2005, assuming all approvals
are granted. This centre is fully operational including
a clinical centre and of the state-of-the art immunology
laboratory entirely dedicated to clinical trials. The
second AIDS vaccine clinical evaluation centre is
being set up at the Tuberculosis Research Centre,
Chennai. A Phase I trial with the MVA vaccine is
expected to begin in 2005.
The implementation of clinical trials to test the
vaccine efficacy is the bottleneck of clinical
development for any vaccine, in particular for AIDS
vaccines. Such implementation represents a
tremendous scientific and organisational challenge that
must be anticipated years in advance. An important
step is therefore to define the feasibility of such trials
in India. In this regard, assessments of various
infrastructures and organisations working with
different communities and their epidemiological
characteristics were conducted by a team comprising
of several national and international experts. The team
visited select scientific institutions and non-
governmental organisations in view of providing
recommendations for the conduct of site and
community preparedness studies.
The AIDS vaccine development programme in
India is based on transparency and accountability. To
ensure that the trials are ethical and safe, broad-based
community support is required. Several mechanisms
and bodies have been put in place including the: (i)
National AIDS Vaccine Advisory Board providing
guidance to the Government of India. (ii) Informed
Consent Group to develop a template for the Informed
Consent documents used in the Phase I trials; (iii)
Gender Advisory Board and Training to help oversee
and guide the Indian vaccine programme’s efforts to
incorporate gender concerns in AIDS vaccine trials.
Training modules and a framework for implementing
gender training for trial staff was developed with their
assistance; (iv) Non-Governmental Organisation
Working Group to ensure that communities are better
informed of the clinical trial processes and that the
trials are conducted in a safe and ethical manner with
community support and representation; and  (v)
National Consultation on HIV Care and Treatment in
AIDS Vaccine Trials. The consultation helped define
the policy and technical guidelines for the care and
treatment of trial participants, including those who
become HIV infected, during the course of AIDS
vaccine clinical trials, within the larger framework of
the NACO HIV/AIDS care and treatment policy
guidelines.
Conclusion
The quest for an AIDS vaccine presents an
unprecedented scientific and human challenge for this
21st century. AIDS vaccines must be seen as the
ultimate prevention tool that will complement the
existing prevention strategies. The acceleration of
vaccine development through the parallel exploration
of several scientific approaches and implementation
of clinical trials are the best and probably only way
to reach this goal. This long-term commitment
endeavour requires strong and renewed political
leadership and commitment, flexibility of processes,
medical and scientific dedication and collaboration on
a mission mode along with community participation
for immediate action. The recent achievements in
India highlight clearly the commitment of the
Government of India and the scientific community to
a long-term global effort to develop an AIDS vaccine.
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Reprint requests: Dr Jean-Louis Excler, Medical Director, International AIDS Vaccine Initiative, India,
193, 1st Floor, Jor Bagh, New Delhi 110003, India
e-mail: jlexcler@iavi.org