Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development?

Abstract

Since the discovery of HIV vaccine three decades back, the quest for HIV vaccines has remained unquenched. There has been a transition of preferred approaches from candidates capable of inducing neutralizing antibody (Nab) or cytolytic T cell (CTL) response to vaccines that can induce broad spectrum responses. Heterologous prime boost strategy is believed to induce broad spectrum immunity of higher magnitude and breadth to effectively counter HIV diversity and hence is being studied extensively in the HIV vaccine field. It is important to understand factors affecting the immune responses generated by the prime-boost regimens to get leads for developing effective regimens. This review focuses on the results of completed clinical trials based on the three most frequently used prime-boost regimens, vector (ALVAC)/protein, DNA/vector (MVA) and DNA/vector (Ad5). It will also discuss probable protective immunological responses responsible for efficacy of the vaccine and role of prime boost strategy in eliciting them.

Full text

Volume 5 • Issue 4 • 1000294
Open Access
Review Article
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal
Shete et al.,
J AIDS Clin Res 2014, 5:4
http://dx.doi.org/10.4172/2155-6113.1000293
AIDS & Clinical
Research
Vaccine Research: HIV
Is Prime Boost Strategy a Promising Approach in HIV Vaccine
Development?
Ashwini Shete1, Madhuri Thakar1, Sanjay Mehendale2 and Ramesh Paranjape 1*
1National AIDS Research Institute, Indian Council of Medical Research, 73, G block, MIDC, Bhosari, Pune-411026, India
2National Institute of Epidemiology, Chennai, India
*Corresponding author: Paranjape RS, Director, National AIDS Research
Institute, Indian Council of Medical Research, 73, G block, MIDC, Bhosari,
Pune-411026, India, Tel: +91-20-27331200; Fax: +91-20-27121071; E-mail:
rparanjape@nariindia.org
Received February 27, 2014; Accepted April 11, 2014; Published April 21, 2014
Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost
Strategy a Promising Approach in HIV Vaccine Development? J AIDS Clin Res 5:
293. doi:10.4172/2155-6113.1000293
Copyright: © 2014
Shete A, et al
. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Keywords: CTL response; Envelope; Heterologous HIV vaccine;
Neutralizing antibody; Prime-boost Strategy; Protein subunit; Vector
Introduction
HIV prevention strategies to reduce the spread of HIV remain a
global public health priority. An eective HIV vaccine, if available,
would have several advantages over behavioral and other biological
prevention strategies as it would not need sustained behavior changes
as well as strict adherence for the ecacy, in addition to probably
providing long term protection. Although inactivated and live
attenuated vaccines are being eectively used for other viral infections,
they are not being considered favorably in case of HIV because of safety
concerns. Hence most of the eorts towards HIV vaccine development
have been focused on newer strategies such as synthetic envelope
protein subunits or recombinant viral vectors carrying HIV-specic
inserts or naked DNA [1]. Although most of these vaccine candidates
have failed to elicit eective immune responses when used alone [2,3],
their combined use has been shown to strengthen and broaden HIV-
specic immune responses [4-6]. Such a combination strategy is known
as prime-boost strategy where the immune system primed by one
vaccine candidate is boosted with either the same (homologous) or a
dierent (heterologous) vaccine candidate.
More than 100 non human primate and human clinical trials have
been conducted so far to test the safety, immunogenicity and ecacy of
dierent combinations of vaccine candidates [7]. e results of clinical
trials have oen been shown to dier from those seen in animal studies
indicating critical need for reviewing them to understand the immune
responses elicited by the vaccine candidates for use in humans [8].
Hence this review is focused on discussing the outcomes of dierent
prime boost HIV vaccine clinical trials and factors responsible for
them, which would have implications in guiding future vaccine trials
based on prime boost strategy.
Basis of Prime Boost Strategy
Boosting of immune responses by vaccines results in generation
of larger numbers of eector cells required for mediating protection
against pathogens at the time of infection [9]. Homologous strategy
eectively boosts the humoral immunity but fails to boost cellular
immunity (CMI). While heterologous prime-boost approach is
known to eectively boost CMI, especially when vector based vaccine
candidates are used, as it minimizes the interference by anti-vector
immunity generated aer priming (illustrated in Figure 1). Apart from
enhancing the eector cells quantitatively, qualitative dierences in
secondary memory cells are also seen aer the boosting. Secondary
memory CD8 T cells, in contrast to primary memory cells, trac much
more eciently to peripheral tissues and exhibit enhanced cytolysis
facilitating eective countering of pathogens at the site of entry [10].
Additionally, heterologous prime boost strategy results in synergistic
enhancement of immune response resulting in an increased number
of antigen-specic T cells, selective enrichment of high avidity T cells
and increased breadth as well as depth of the immune response [11,12].
However, heterologous prime boost regimens are still at the stage of
clinical research and no regimen has been adopted in the immunization
programs until now, as the critical evidence of translation of all these
advantages is lacking. One of the major limitations of the prime boost
strategy is its complex design. Multiple factors can contribute to its
ecacy, which include combination of vaccine candidates, order of
their administration, vaccine dose, interval between various antigen
exposures, route of vaccine administration, pre-existing immunity to
the vectors and relatedness of epitopes between the prime and booster
antigens. Other limitations of the strategy include the requirement
of multiple dosages of dierent vectors which might add to potential
side eects and could be challenging for a vaccination programme.
A phenomenon of ‘original antigenic sin’ may also occur where by
immune response to original antigens present in the prime interfere in
Abstract
Since the discovery of HIV three decades back, the quest for HIV vaccines has remained unquenched. There has
been a transition of preferred approaches from candidates capable of inducing neutralizing antibody (Nab) or cytolytic
T cell (CTL) response to vaccines that can induce broad spectrum responses. Heterologous prime boost strategy is
believed to induce broad spectrum immunity of higher magnitude and breadth to effectively counter HIV diversity and
hence is being studied extensively in the HIV vaccine eld. It is important to understand factors affecting the immune
responses generated by the prime-boost regimens to get leads for developing effective regimens. This review focuses
on the results of completed clinical trials based on the three most frequently used prime-boost regimens, vector
(ALVAC)/protein, DNA/vector (MVA) and DNA/vector (Ad5). It will also discuss probable protective immunological
responses responsible for efcacy of the vaccine and role of prime boost strategy in eliciting them.

Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
Page 2 of 9
Volume 5 • Issue 4 • 1000293
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
the response elicited to new antigens present in the boost, if dierent
insert sequences are used for priming and boosting [13].
Clinical trials of HIV-1 candidate vaccines using prime boost
strategy
HIV vaccine trials are primarily focused on generation of
neutralizing antibodies to prevent the establishment of infection or
generation of T-cell responses eective in reducing viral burden in the
post-infection phase [14,15]. However, since both these strategies alone
failed to show protection from HIV infection [2,3,16], their combination
was thought to be benecial for protection and hence was evaluated
in clinical trials by combining dierent strategies. e most frequent
combinations tested in clinical trials include vector prime protein boost
and DNA prime vector (pox or adenovirus) boost combinations.
Vector prime protein boost
Clinical trials carried out using vector prime protein boost regimen
have mainly focused on the pox virus vectors for priming. Pox virus
vector constructs have the ability to induce CTLs in humans but
they have not been shown to elicit high-titer neutralizing antibodies
[4,17,18]. However, the use of an envelope protein boost aer the pox
vector prime has been reported to generate higher levels of binding
and homologous neutralizing antibodies in addition to development
of antibody-dependent cell mediated cytotoxicity (ADCC), and
helper T cell responses in several phase I clinical trials [18-20]. Non-
replicating poxvirus vectors, including Modied Vaccinia Ankara
(MVA), and the genetically modied NYVAC vector, fowl pox and
canary pox (ALVAC) vectors are preferred in clinical trials over
replication competent vaccinia vector because of its safety concerns and
poor immunogenicity, possibly due to existing anti-vector immunity
resulting from global smallpox vaccinations [21,22]. Among all pox
viruses, several Canarypox vector based constructs with multiple HIV-
1 gene inserts have undergone extensive safety and immunogenicity
studies in humans [23,24]. Although the Canarypox prime-protein
boost regimens have been shown to induce increased frequency and
magnitude of HIV-1 lympho-proliferative activity, neutralizing activity
and ADCC, the CTL responses induced by them were limited. Hence,
several modications have been made in the construct to improve
CTL responses as illustrated in Figure 2. A phase III trial, RV144,
using Canarypox (vCP1521) prime and AIDSVAX B/E boost has
demonstrated modest protective ecacy when tested in ailand
[25]. But this strategy failed to control viremia or CD4 cell loss aer
the breakthrough infections among those who received the vaccines
indicating inability of this strategy to alter the course of the disease. e
protection in RV144 trial appeared to be short lasting, [26] and it would
be interesting to evaluate the eect of additional boosters in RV144
trial participants on recall responses and continuing protection among
them. Indeed, in the AVEG studies (AIDS Vaccine Evaluation Group),
a recall antibody response aer delayed rgp160 boost at 4-5 years of
ALVAC vaccinations has indicated induction of long term memory B
Priming Immunization
Booster Immunization
Vector 1
Exogenous angen presentaon
Plasma cell
Antibody response
Endogenous angen presentaon
Cell mediated response
Infecon/ Transfecon of cells
other than APCs Uptake by APCs
Shedding of
angens necroc
bodies
MHC II
MHC I
TH2 TH1
B cell CD8
CTL
Heterologous
(Vector 2)
B
cell
TH2 TH1 CD8
CTL
Less infecon or uptake by
host cells
Exogenous angen
expression by the
vector not much affected
Boosng of insert
specific anbody
response
Reduced boosng of
insert specific cell
mediated response
Infecon or uptake by
host cells not affected
Exogenous angen
presentaon not
affected
Boosng of insert specific anbody and cell
mediated responses
Homologous
(Vector 1)
Elimination of vector by
immune responses
induced against vector 1
by priming
No interference by
immune responses
induced against
vector 1 by priming
Figure 1: The role of heterologous prime boost strategy in overcoming anti-vector immunity
Vector based vaccine candidates infect host cells including antigen presenting cells. Induction of immune response depends on antigen presented by host cells after
uptake of the vector. Cellular and humoral immune responses are induced against vector and insert specic antigens through class I and class II MHC molecules,
respectively, upon the antigen presentation. After boosting of immune response with the same vector, uptake of the vector by host cells gets hampered because of
elimination of the vector by anti-vector immunity. This further affects antigen presentation and boosting of insert specic immune responses by the vector. Conversely, if
a different vector is used for boosting, anti vector immunity induced by the prime cannot eliminate an antigenically different vector. Hence, the uptake as well as antigen
presentation by the host cells is not affected, leading to boosting of insert specic immune responses.

Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
Page 3 of 9
Volume 5 • Issue 4 • 1000293
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
cell responses [27].
DNA prime and & Poxvirus vector boost strategy
DNA prime-viral vector boost regimens have become the primary
choice for inducing T cell based immune responses [11,28,29]. Among
all Poxvirus vector based vaccines, MVA based vaccines have been
evaluated in combination with DNA priming in multiple clinical trials.
However, the MVA vectors used in dierent trials diered from one
another in terms of passage numbers, insertion sites, type of promoter
used and the inserted HIV genes leading to non-comparability of the
results reported in dierent clinical trials [30]. Advantage of adding the
DNA prime to MVA based regimen remains questionable as it has been
shown to induce only marginally higher T cell responses as compared
to the homologous MVA boosting strategy [31,32]. Also antibody
responses induced by the DNA/ MVA strategy were found to be inferior
as compared to those induced by the homologous MVA boosting
strategy [31,32]. Among the other poxvirus based vaccines evaluated
in clinical trials, NYVAC based regimens appear to be promising in
eliciting the immune responses [33-35]. On the other hand, fowl pox
based regimens have been shown to be poorly immunogenic in humans
[36,37] while they induced eective CD4 and CD8 T-cell responses in
animal models [38].
Strategies using DNA and Adenoviruses
Among the Adenoviral vector vaccine candidates, replication-
defective Ad5 candidate developed by the Merck group has been
studied most extensively in human trials. is construct demonstrated
good immunogenicity in Phase I clinical trials and reduced viral load
in the SHIV/NHP model [13,39-42]. However, it failed to prevent new
infections as well as to reduce post-infection viral RNA levels in the
vaccinated individuals in phase IIb, test-of-concept, STEP trial [16]. In
addition, participants with pre-existing antibodies against Ad5 vector
showed increased HIV infection rates in the study, the cause of which
is being evaluated at present. e pre-existing immune responses might
have played a role in this as they are known to interfere in the HIV
specic immune responses induced by Ad5 vector [41]. High rates of
pre-existing humoral immunity (as high as 85% in South Africa) to Ad5
have been shown in many parts of the world [43]. e heterologous
prime boost strategy using DNA prime and Ad5 boost was thought to
circumvent the problem of pre-existing immunity. It has been shown
that the pre-existing Ad5 neutralizing antibodies did not aect the
frequency and magnitude of T cell responses in the DNA/rAd5 prime-
boost recipients, as compared to participants who received rAd5 alone
[44]. Although there are conicting reports regarding the increased
magnitude of immune response by DNA/Ad5 strategy over Ad5
vaccine alone, the strategy was successful in inducing both CD4 and
CD8 responses contrary to the DNA and Ad5 vaccine candidates alone
which generated only CD4 or CD8 responses respectively [45,13]. Since
the broad spectrum immune response consisting of both CD4 and CD8
responses is desirable for protection against HIV, this strategy has been
considered to be more suitable than homologous Ad5 vaccinations.
However, in spite of robust immune responses induced by DNA/Ad5
strategy in phase I and phase II trials [46], the strategy failed to show
protection from new infections in a phase IIb, HVTN 505 trial, which
had to be terminated prematurely [47]. Unfortunately the HVTN
505 trial, like the STEP trial, showed a statistically insignicant trend
towards more infections among the vaccine recipients [48].
Other adenovirus serotypes like Ad26 and 35, less commonly
associated with human disease, are also being explored as vaccine
candidates to obviate the interference from pre-existing immunity
against Ad5 [49]. However, Nabs to Ad5 have also been shown to
hamper CD4+ T-cell responses to DNA/rAd35 combination [50].
Factors aecting immunogenicity endpoints of the prime
boost regimens
e clinical trials described in the preceding paragraphs diered
gp160
MN
vCP125
vCP205
gag, Env and protease
To enhance CTL response
vCP300
gag, Env,protease +
nef & pol CTL
epitopes
gag, Env and protease
+ vaccinia coding sequences
(E3L and K3L)
To enhance CTL
response further
vCP1452
To enhance the
expression
efficiency
vCP1521
Gp120 (CRF01_AE)+ gag,
protease (B)
To include env from
CRF_ AE for testing
in AE prevalent area
Less CTL response Improved CTL
response
Further improvement
of CTL response
No improvement of
CTL response
No further
improvement of CTL
response, 31%
efficacy in RV144
trial
Figure 2: The ALVAC–HIV constructs evaluated in combination with protein boost in clinical trials
Different ALVAC construct developed and used as a prime in association with protein boost are shown in the gure. Different HIV genes inserted in these constructs
are mentioned at the bottom of each construct.

Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
Page 4 of 9
Volume 5 • Issue 4 • 1000293
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
from each other in terms of vaccine candidates used, doses, schedule,
route and mode of vaccination as well as the population in which
the trials were conducted. Understanding these factors would help
in optimizing the vaccination schedule to obtain high and persistent
immune responses.
Vaccine dose
Dose of a prime candidate may not be important as it was not found
to inuence the nal immunogenicity results in the trials with all the
three types of regimens [17,45,51]. is could be possible because higher
antigen doses at priming generally favor the induction of eector cells,
whereas lower doses may preferentially drive the induction of immune
memory [52]. Hence higher dose of a prime, although desirable for
immediate responses, may aect development of memory cells and
adversely hamper the eect of high dose. Contrary to the prime dose,
higher dose of the booster has been shown to induce higher magnitude
of immune response in ALVAC/protein and DNA/MVA trials [51,53]
as the greater availability of antigen might be driving higher number of
memory B cells into dierentiation, thereby amplifying the response.
However, this eect was not seen when DNA/AD5 strategies with Ad5
doses of 1010 and 1011 were compared [46]. is could be because of
development of immune tolerance at such high doses. Similar results
were also observed when only Ad5 based strategy was evaluated in a
clinical trial [54].
Immunization schedule
It was observed that late boosts at 5 and 6 month interval induced
higher T cell response as compared to the early boosts given at 2 and
3 months interval in one of the trials with DNA/MVA prime/boost
regimen [55]. e delayed boosting is helpful in avoiding interference
in the primary responses induced by the prime [52]. It has been
observed that although closely spaced (1–2 weeks) primary vaccine
doses cause a rapid induction of immune response, the response is less
persistent than when the same numbers of vaccine doses were given at
longer intervals (1–2 months) [52]. A minimal interval of 4–6 months
may also ensure optimal anity maturation of memory B cells [52].
One of the DNA/Ad5 trials showed that the boosters, as late as at 35
and 94 weeks, also increased the frequency and magnitude of T cell and
antibody response [45], which was, in fact, better than in the other trials
which employed boosting at 24 weeks.
e number of doses required for inducing optimal immune
response may dier based on the vaccine candidate. It has been found
that 4 doses of ALVAC and 2 doses of DNA were optimum for inducing
CTL and CD4 helper T cell responses respectively when used for
priming [56,57]. ere are conicting reports regarding the number of
MVA doses required for boosting. One study reported higher T cell
response rate aer 2 MVA doses [56], whereas diminution of response
rate and magnitude aer second MVA dose was reported in another
trial [58]. Number and timing of protein boosts diered considerably
in ALVAC/protein based trials as multiple combinations were
evaluated with either sequential or simultaneous boosting. Although
the simultaneous boosting showed early antibody responses [59],
sequential boosting schedules were reported to elicit higher magnitude
of neutralizing antibody response [57].
Route of administration and delivery systems used
Dierent routes and delivery systems have been evaluated for
DNA constructs in prime–boost strategy. It has been shown that DNA
constructs, administered by intra-dermal route induced better immune
response compared to the intramuscular or subcutaneous routes
[60,61]. Immunogenicity of DNA constructs depends on processing
and presentation of antigens by antigen presenting cells (APCs) and
the skin, unlike muscle tissue, has a large population of resident antigen
presenting cells (APCs) that can facilitate the induction of vaccine-
specic immune responses [62,63]. Biojector and electroporation for
delivering DNA have also shown to enhance antigen presentation by
targeting larger area and enhancing uptake by the cells by the transient
formation of pores in the cell membrane, respectively [62,64]. e
biojector delivery system was observed to be better than administration
by needle/ syringe as well as by electroporation in two HIV clinical
trials [58,65]. A combination of biojector and electroporation has been
shown to overcome dose restriction of DNA vaccines in preclinical
studies whereby immune responses were shown to be enhanced when
the dose of DNA was increased in clinical trials [66].
Adjuvants
Adjuvants are components of vaccines used for potentiating and/or
modulating the immune responses to anantigen. Since DNA vaccines
are weakly immunogenic, dierent adjuvants like Al3PO4 or CRL1005
and immuno-modulators like GM-CSF were evaluated for enhancing
their immunogenicity in the prime boost trials without success [13,51].
ese adjuvants had shown promising eects in animal studies [51].
is also highlights the importance of determining immune responses
in clinical settings. One of the trials which evaluated two adjuvants
namely MF59 and Alum for the protein boosting showed that MF59
adjuvanted protein subunit candidate induced better response than
using Alum as an adjuvant [53,67]. MF59 has also shown to be more
potent than alum based adjuvants in inducing both antibody and T-cell
responses when evaluated as an adjuvant for u vaccine and is being
currently used in u vaccine preparations [68].
Pre-existing immunity against the vectors
Prime boost strategy has been thought as one of the ways to
circumvent the pre-existing immunity to vectors. However, DNA/
Ad5 based clinical trials have provided inconclusive evidence in this
regard [44,13]. For ALVAC/protein based strategy, one study reported
no signicant dierences in frequency or level of immune responses
to ALVAC (with or without protein boost) between Vaccinia-naive
or Vaccinia immune individuals [17], while another study reported
decreased magnitude of Nabs in Vaccinia immune individuals
compared to Vaccinia-naive [57]. Lower magnitude of cellular immune
responses in persons with a history of Vaccinia vaccination has been
reported in one of the DNA/MVA trials, which has been thought to
be contributed additionally by eect of age in these individuals [51]
indicating multifactorial etiology responsible for such variations.
Relatedness of insert sequences or heterologous inserts
Not enough clinical data are available for comparing immune
responses induced by heterologous insert sequences. e results of the
ALVAC/protein based clinical trials having insert gp120 sequences from
the same or dierent strains of HIV-1 do not dier much from each
other. Although they are thought to improve global epitope coverage or
cellular immune breadth, they failed to demonstrate this in an animal
study [69]. e phenomenon of original antigenic sin also needs to be
kept in mind before devising strategies based on heterologous inserts.
Can Prime Boost Vaccine Strategy Full the Possible Criteria
for an Ideal HIV Vaccine to be Protective?
Although immunogenicity results are available from multiple phase
I and II trials based on the prime boost strategy, they are not sucient

Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
Page 5 of 9
Volume 5 • Issue 4 • 1000293
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
to predict the ecacy of the strategy. Analyses of immune responses
observed in large scale ecacy trials are, therefore, important as they
are likely to provide clues about protective immune responses in HIV
infection. e dierence in the immune responses elicited in RV144
prime boost trial that demonstrated modest protection and VAX003/
VAX004, AIDSVAX alone, trials need to be carefully analyzed to
delineate the factors that might have contributed to the protection.
Based on results of such ecacy trials as well as data from animal
studies using SIV challenge, dierent factors that possibly play role in
ecacy of the immune response can be deciphered.
Type of immune response
Although broadly neutralizing antibodies are considered to be an
important component of vaccine induced immune responses, it has
not been possible to induce them in any of the clinical vaccine trials
conducted so far. Antibody based phase III vaccine trials have utilized
monomeric gp120 presenting linear antigens, not considered to be
optimum for induction of neutralizing antibodies. Since conformational
epitopes are considered to be more potent in inducing neutralizing
antibodies, candidates presenting envelope antigens in their native
conguration would be more appropriate for vaccine development.
Virus-like particles and trimeric gp140 antigens have shown promise
in induction of neutralizing antibodies [70,71] and can be employed in
prime boost combinations for eectively inducing broadly neutralizing
antibodies.
Non-neutralizing antibodies have also been shown to play a role
in protection from HIV infection in the RV144 trial. IgG antibodies
specic to the V1/V2 region of HIV-1 gp120 correlated with a decreased
risk of infection with evidence of a virus sieve eect in infected vaccine
recipients at this gp120 region [72,73]. Although the exact mechanism
mediating protection by these antibodies in the trial is not yet known,
they are thought to block T-cell associated integrin, a4b7, which is
involved in HIV-1 entry in activated CD4+ T-cells [74,75]. e role
of these antibodies in mediating protection from HIV needs to be
conrmed further.
As against the neutralizing antibodies, responses like CTLs and
ADCC act aer infection of the cells and eliminate the infected cells
decreasing overall burden of HIV by blocking further multiplication
of virus. RV144 trial data showed that high level of ADCC activity
was inversely correlated with infection risk. For mediating such
activity, specicity and Fc related functions of the antibodies would
be the important determinants. Antigens expressed on cells would be
important for mediating ADCC activity and it may be possible that
these antigens were expressed by infected cells upon uptake or infection
by ALVAC vector and antibodies against them were subsequently
boosted by gp120 protein boost. It was also observed that the IgG
isotypes in case of RV144 trial participants were IgG1 and IgG3, which
have the ability to bind and stimulate the NK cells eciently through
binding with CD16 [76]. Compared to the RV144 results, VAX003 trial
participants had higher titres of IgG4, which show poor ADCC activity
[76]. e future vaccine trials based on vector prime protein boost
strategy should be equipped to explore the role of ADCC activity in
the protection.
Like ADCC, CTLs are also important in eliminating HIV infected
cells and their role in controlling HIV progression has been well
documented from studies on Long Term Non Progressors (LTNPs),
exposed but uninfected individuals and in non human primate models
[77-79]. However, it has not been possible to attribute a role to CTLs
in controlling HIV infection in clinical vaccine trials conducted so far.
In theRV144 trial showing moderate protection, a CTL response was
reported in only 19.7% of vaccinees [25]. On the other hand, the Ad5
based STEP and HVTN 505 trials failed to prevent HIV-1 infection or
reduce early viral level, in spite of induction of a CTL response in 75%
and 64% of the vaccinees respectively [16,47]. However, despite the lack
of vaccine ecacy in the STEP trial, participants with specic human
leukocyte antigen (HLA) alleles demonstrated an evidence of vaccine-
elicited immune pressure on the founder virus resulting in specic
escape mutations. ey also had lower viral load highlighting the role
of CTL response in controlling viral multiplication in the trial [80].
Dynamics of immune response
Antibodies are usually long-lived and hence once generated are
usually available at the time of exposure to deal directly with the incoming
viral inocula resulting in protection [81]. However, this is not the case
with CTL based vaccines. Eectors and eector memory cells (TEM),
which are considered to be important for immediate action against
any pathogen are short lived and tend to disappear aer the clearance
of the antigens leaving behind central memory T cells (TCM). Hence
soon aer vaccination with the non persistent vaccine candidates, only
TCM type of cells persist, which shows inherent delay in development
of anti-viral eectors limiting the utility of CTL based vaccines [81]. On
the contrary, persistent vectors like Rhesus cytomegalovirus (RhCMV)
were shown to induce persistent, high-frequency, SIV-specic TEM
responses at mucosal sites resulting in stringent control of highly
pathogenic SIVMAC239 infection aer mucosal challenge in rhesus
macaques when used alone or in prime boost combination [82,83].
Hence the use of persistent vectors needs to be evaluated further in
clinical trials for developing of eective CTL based vaccines. However,
such vaccine approaches also carry a risk of developing CD4 TEM
providing a higher frequency of activated target cells at mucosal sites
[81]. Hence vaccine regimens eliciting a predominant CD8 response
would be important for balancing potentially infection-suppressing
and infection-facilitating mechanisms.
Site of immune response
Mucosal immune responses are considered to be important for
restricting the virus multiplication at the site of entry before systemic
dissemination occurs. e factors which favor development of
mucosal immune responses include the mucosal or trans cutaneous
immunization and the replicating nature of the vaccine agents [84,85].
A prime boost strategy with heterologous routes of administration
based on the combination of mucosal and parenteral delivery has
been attempted in a murine model for inducing immune responses
at both mucosal and systemic levels [86]. Although mucosal route for
vaccination is desired for its ease of administration and development
of local immunity, mucosal vaccinations are faced with safety concerns
and problems of lesser ecacy [87]. erefore, only a few vaccines
have become available for mucosal use until now. Since many of the
HIV vaccine trials have used live viral vectors and percutaneous
route, mucosal immune responses might have been generated in the
vaccinees. Unfortunately information on mucosal immune responses
in HIV vaccine clinical trials is scarce. It is important that the future
trials should assess immune responses generated at the mucosal level.
Prime boost strategy has also been shown to generate secondary
memory cells which tend to localize in peripheral tissues causing
eective an immune response at the site of infection [10]. However,
these cells tend to localize poorly in lymph nodes which are the major
sites of HIV replication [10]. Hence these cells may not play a role
in controlling viremia once the virus escapes the mucosal immune

Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
Page 6 of 9
Volume 5 • Issue 4 • 1000293
J AIDS Clin Res
ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
responses. Hence it would be important to balance mucosal as well as
systemic T cell responses in order to eectively control the infection.
Other limitations of mucosal immune responses include generation
of activated CD4 cells at mucosal sites, which might serve as potential
targets for HIV infection. Also mucosal reactions can increase blood-
borne IgA secreting plasma cells which are known to be derived from
mucosal immune responses [88]. HIV-1 Env-specic plasma IgA
responses have shown direct correlation with HIV infection risk in
the RV144 trial, which could be by blocking protective IgG antibodies
mediating ADCC activity [89].
Magnitude of immune response
Potent immune responses of higher magnitude are desirable to deal
with a higher inoculum of the virus. Prime-boost combination vaccines
have been found to elicit a dramatic enhancement in the magnitude of
anti-viral CD8+ T cell responses aer infection (oen >10-fold) [81].
Hence a prime boost strategy can be used for enhancing potency of the
cell mediated immune responses.
Breadth of immune response
e vaccine strategies that expand breadth of cellular immune
response have been considered to be critical for achieving immunologic
coverage of the enormous global genetic diversity of HIV-1 [90].
Importance of breadth of immune response has also been highlighted
from studies in chronically infected patients and macaque models
[91,92]. e STEP trial, which failed to show protection, demonstrated
limited breadth of response [93]. To increase the breadth of response and
to cover global HIV-1 sequence diversity, polyvalent 'mosaic' antigens
have been designed, which have been shown to induce markedly
augmented breadth and depth of response without compromising
the magnitude of T cell responses in Rhesus monkeys [90]. Protective
ecacy of the mosaic antigens has also been demonstrated in Macaques
[94]. Clinical studies evaluating Ad26/MVA regimens expressing HIV
-1 mosaic antigens have been planned and would provide clinical data
in this regard.
Immune responses against conserved epitopes
Targeting conserved epitopes by the immune response has also
been considered to be an important component of vaccine induced
immunity to overcome HIV diversity and mutations. However,
conserved epitopes have been found to elicit subdominant responses
during both primary and chronic infection [95] as well as in a vaccine
trial. e immune response has been seen to be biased towards non
conserved epitopes, which might mask responses to conserved epitopes
enabling HIV to escape immune surveillance mechanisms [96].
e prime boost strategy could be exploited to boost specically the
responses against the conserved epitopes by using these epitopes in the
boost candidates.
Analysis of correlate of risk
As against the correlates of protection, analysis of correlates of
increased risk of HIV acquisition has become imperative as a result
of ndings in Ad5 based STEP and HVTN 505 trials. e STEP study
reported an increased risk of HIV acquisition among MSM who were
uncircumcised or had neutralizing antibodies to Ad5 at the enrolment
[16]. In spite of extensive research to identify biological reasons for
such an increased risk, no evidence is available yet. e subgroups
of participants showing enhanced risk in STEP trial were excluded
from HVTN 505 trial. However, a trend of increased risk of HIV
acquisition was also reported in the HVTN 505 trial demonstrating
the susceptibility of these subgroups for the enhanced risk. Based
on the HVTN 505 results, the results of the STEP trial also need to
be re-evaluated with a dierent focus as the pre-existing immunity
against Ad5 alone may not be playing a role in enhancing the risk of
HIV acquisition. Possibility of occurrence of such a risk with other
adenovirus serotypes should also be ruled out before proceeding to the
clinical trials using these constructs.
Conclusion
e available evidence suggests that the heterologous prime-boost
vaccination approach has some promise in HIV vaccine development.
However, the prime-boost strategy has major operational and analytical
complexities. Also the ecacy results have churned out surprises quite
in contrast to the preclinical as well as immunogenicity data available
from phase I and II trials. is may be due to the lack of conrmed
knowledge about the correlates of protection in HIV infection. Hence,
analysis of correlates of protection is critical for designing eective
vaccine trial strategies. Two vaccine ecacy trials based on prime boost
strategy, the RV144 and HVTN 505 trials, have demonstrated exactly
opposite outcomes. e results of these trials need to be evaluated
carefully to determine correlates of protection and increased risk of
HIV acquisition for balancing protective and enhancing mechanisms
in future vaccine trials. Up till now, only RV144 vaccine trial has been
successful in demonstrating moderate, but short lasting protection
against HIV infection. e search for the most appropriate regimen for
eliciting eective and sustained immune responses must be continued
till an eective preventive vaccine strategy is devised.
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Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development? J
AIDS Clin Res 5: 293. doi:10.4172/2155-6113.1000293
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ISSN: 2155-6113 JAR an open access journal Vaccine Research: HIV
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This article was originally published in a special issue, Vaccine research: HIV
handled by Editor(s). Dr. Marc Van Regenmortel, University of Strasbourg,
France
Citation: Shete A, Thakar M, Mehendale SM, Paranjape RS
(2014) Is Prime
Boost Strategy a Promising Approach in HIV Vaccine Development? J AIDS
Clin Res 5: 293. doi:10.4172/2155-6113.1000293
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