Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary

Bonsignori, Mattia

Brown, Brita

Brown, Scott A

Coleclough, Chris

Freiden, Pamela J

Hurwitz, Julia L

Jones, Bart G

Sealy, Robert

Slobod, Karen S

Stambas, John

Surman, Sherri

Zhan, Xiaoyan

Zirkel, Amy

English

PubMed

Karen S Slobod

Chris Coleclough

Scott A Brown

John Stambas

Xiaoyan Zhan

Sherri Surman

Bart G Jones

Amy Zirkel

Pamela J Freiden

Brita Brown

Robert Sealy

Mattia Bonsignori

Julia L Hurwitz

Springer - Publisher Connector

Abstract Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary.</p

Zirkel Amy

Jones Bart G

Surman Sherri

Zhan Xiaoyan

Stambas John

Brown Scott A

Coleclough Chris

Slobod Karen S

Freiden Pamela J

Brown Brita

Sealy Robert

Bonsignori Mattia

Hurwitz Julia L

Directory of Open Access Journals

AIDS Research and Therapy

Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?

BioMed CentralAIDS Research and Therapy
ssOpen AcceHypothesis
Clade, Country and Region-specific HIV-1 Vaccines: Are they 
necessary?
Karen S Slobod1,3, Chris Coleclough2,4, Scott A Brown1, John Stambas5, 
Xiaoyan Zhan1, Sherri Surman1, Bart G Jones1, Amy Zirkel1, 
Pamela J Freiden1, Brita Brown1, Robert Sealy1, Mattia Bonsignori2,6 and 
Julia L Hurwitz*1,4
Address: 1Department of Infectious Diseases, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105 USA, 2Department of 
Immunology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105 USA, 3Department of Pediatrics, College of Medicine, 
899 Madison Ave., University of Tennessee, Memphis, TN 38163 USA, 4Department of Pathology, College of Medicine, 899 Madison Ave., 
University of Tennessee, Memphis, TN 38163 USA, 5Department of Microbiology and Immunology, University of Melbourne, Vic 3010, Australia 
and 6Department of Clinical and Biological Sciences, University of Insubria, Varese, 21100, Italy
Email: Karen S Slobod - karen.slobod@stjude.org; Chris Coleclough - chris.coleclough@stjude.org; Scott A Brown - Scott.brown@stjude.org; 
John Stambas - jstambas@mail.staff.unimelb.edu.au; Xiaoyan Zhan - Xiaoyan.zhan@stjude.org; Sherri Surman - Sherri.surman@stjude.org; 
Bart G Jones - bart.jones@stjude.org; Amy Zirkel - zirk11@yahoo.com; Pamela J Freiden - pam.freiden@stjude.org; 
Brita Brown - brita.brown@stjude.org; Robert Sealy - bob.sealy@stjude.org; Mattia Bonsignori - mattia_b@elitel.biz; 
Julia L Hurwitz* - julia.hurwitz@stjude.org
* Corresponding author    
Abstract
Today, scientists are often encouraged to custom-design vaccines based on a particular country or
clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor
to produce a unique vaccine for every world region or virus subtype may not be necessary.
Clade, country or region-specific vaccines
It is generally agreed that HIV-1 arose decades ago by
transfer of virus from chimps to humans [1]. The subse-
quent travel of infected persons and the continued prac-
tice of high-risk behaviors fostered virus transmission to
virtually every world region. Once HIV-1 awareness was
heightened and HIV-1 sequencing projects were imple-
mented, regional similarities of viral sequences, presuma-
bly a consequence of the founder effect, became evident.
Clade designations (e.g. clade A, B, C) were then used as a
means to categorize viruses based on genetic sequence;
thus such clade designations also tended to cluster viruses
according to geographical location. Today, due to contin-
uous virus transmission, mutation and recombination,
the demarcation of HIV-1 subtypes has become increas-
ingly blurred, and the categorization of viruses by clade is
increasingly difficult [2-5]. Nonetheless scientists are cur-
rently encouraged to custom-design vaccines based on a
particular country or clade [6-11]. To this end, a single
viral sequence may be selected, possibly based on a for-
mula of ancestry or consensus, to represent all other
viruses in the targeted category.
Designing vaccines in this way prompts careful considera-
tion: must a unique vaccine be prepared to represent every
clade, country or region of the world? If so, how will this
be accomplished and for which country should first vac-
cines be produced? Who will decide? The complexity of
Published: 28 April 2005
AIDS Research and Therapy 2005, 2:3 doi:10.1186/1742-6405-2-3
Received: 01 April 2005
Accepted: 28 April 2005
This article is available from: http://www.aidsrestherapy.com/content/2/1/3
© 2005 Slobod et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 3
(page number not for citation purposes)
AIDS Research and Therapy 2005, 2:3 http://www.aidsrestherapy.com/content/2/1/3such an undertaking and the many difficulties that attend
it encourage a second look at the strategy. Review of the
scientific literature may provide reassurance that the
seemingly unachievable endeavor to custom-produce a
vaccine for every clade, country or region may not be nec-
essary.
Do immune responses discriminate between 
clades?
While differences in encoded protein sequence may per-
mit discrimination between certain HIV-1 subtypes, suc-
cessful vaccine development requires that viral proteins
elicit protective immune responses, regardless of
sequence. It has long been known that clades, as defined
by genetic sequence, do not correspond to immunotypes,
as defined by mutually exclusive immune responses [12-
14]. Both B- and T-cells elicited by a virus from one clade
may recognize viruses from other clades. This cross-clade
responsiveness is explained by the fact that the B- and T-
cells recognize precise epitopes rather than the overall
sequence similarity of viruses. Antibody binding depends
on three-dimensional structure, and the molecular struc-
tures bound by antibodies can occur on proteins that dif-
fer widely in primary sequence. T-cells recognize peptides
in association with Class I or Class II MHC molecules, but
like B-cells, T-cells can cross-react with non-identical tar-
gets. Conversely, two viruses may have 99% sequence
similarity, yet a particular neutralizing antibody or T-cell
receptor may discriminate between them. This discrimi-
nation may be due to a single amino acid change within
the receptor contact site or in a sequence that alters
epitope display [15,16]. Thus it is the detail of epitope and
epitope context, not overall sequence similarity that
defines lymphocyte specificity.
Cross-clade protection is achieved by priming 
the immune system with diverse viral sequences 
from a single clade
The issues described above suggest that although a single-
component vaccine may not be sufficient to target any
clade, a cocktail vaccine, designed to represent the natural
diversity of HIV-1, may be sufficient to target all clades.
The latter point is supported by studies of HIV-1-infected
humans and SIV-infected macaques. Although infected
subjects cannot clear endogenous virus (due to its seques-
tration in "privileged" sites, hidden from the immune sys-
tem), most individuals are resistant to super-infection
[17-22]. This protection likely arises as the result of many
successive rounds of endogenous viral mutation in the
infected host. Each time an immune response is elicited in
the periphery of an infected subject, new virus mutants
appear [23,24]. The new viruses, by definition, have
altered T- and B-cell determinants, allowing escape from
the established antibodies and T-cell receptors. Following
several rounds of immune response and virus escape, the
B- and T-cells are primed to recognize a broad spectrum of
determinants [25]. Thus, superinfections are rare, even in
subjects likely to have been serially exposed to viruses
from different clades. The rare double infections in
humans (explaining the origin of virus recombinants [4])
are perhaps a consequence of (i) drug regimens which
block the natural evolution of virus in the infected subject,
(ii) repeated HIV-1 exposures prior to maturation of the
adaptive immune response, and/or (iii) disease-related
immunodeficiency.
The fact that a mature immune response to HIV-1 cannot
clear sequestered virus, but can prevent super-infection
emphasizes the importance of priming the system
preemptively. Similar considerations pertain to the design
of vaccines against human herpesviruses (e.g. VZV and
EBV), as these viruses provoke both lifelong infections
and long-term protective immunity to superinfection. As
with the successful VZV vaccine [26], an effective HIV-1
vaccine should be administered before virus exposure,
infection and sequestration.
Could a cocktail vaccine ever be large enough to 
prevent HIV-1 infections?
Perhaps careful vaccine formulation will preclude the
need for assembly of enormous cocktails. Consideration
that envelope structure is constrained by function suggests
that the formulation of an effective envelope-based vac-
cine is feasible. The virus envelope must bind target cells
to mediate infection, and only a few target cell receptor
molecules (e.g. CD4, CCR5, CXCR4), have been
described. Therefore, the number of discrete envelope
shapes that maintain full cell-binding potential and func-
tion is likely to be limited [27]. Because the virus envelope
is the target of both neutralizing antibodies and T cells,
the strengths of both arms of the immune system may be
harnessed by an envelope-based vaccine cocktail [28-30].
Diverse proteins need not be cross-inhibitory. In fact,
type-specific immune responses have been recognized
toward a single envelope construct represented as only 1%
of a mixed vaccine [31]. Cocktail vaccines are effective in
controlling other diverse pathogens (e.g. pneumococcus,
poliovirus), despite early doubts about their prospect of
success [32].
Clade, Country or Region-specific HIV Vaccines 
may not be necessary
The assembly of envelope cocktail vaccines will probably
be necessary to represent the natural diversity of HIV-1,
even within a single clade. Careful vaccine design may
reveal a cocktail formulation able to prevent virus infec-
tions in every world region, and to overcome the political
and financial dilemmas associated with the production of
clade, country or region-specific vaccines.Page 2 of 3
(page number not for citation purposes)
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Acknowledgements
This work was supported in part by NIH NIAID P01-AI45142, NCI Cancer 
Center Support Core Grant P30-CA21765, the Mitchell Fund, the Feder-
ated Department Stores, the James B. Pendleton Charitable Trust and the 
American Lebanese Syrian associated Charities (ALSAC).
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Slobod, KS

Coleclough, C

Brown, SA

Stambas, J

Zhan, X

Surman, S

Jones, BG

Zirkel, A

Freiden, PJ

Brown, B

Sealy, R

Bonsignori, M

Hurwitz, JL

University of Melbourne Institutional Repository

Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary.<br /

Slobod, Karen S.

Brown, Scott A.

Jones, Bart G.

Freiden, Pamela J.

Hurwitz, Julia L.

Deakin Research Online

Clade, country and region-specific HIV-1 vaccines : are they necessary?

AJ: Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nature Medicine

Application of the polyvalent approach to HIV-1 vaccine development. Current Drug Targets-Infectious Disorders

Cellular immunity to human immunodeficiency virus type 1 (HIV-1) clades: relevance to HIV-1 vaccine trials in Uganda. J Infect Dis

Characterization and selection of HIV-1 subtype C isolates for use in vaccine development. AIDS Res Hum Retroviruses

CJ: Rapid evolution of the neutralizing antibody response to HIV type 1 infection.

Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine.

CV: Neutralizing antibody responses to autologous and heterologous isolates of human immunodeficiency virus. J Acquir Immune Defic Syndr

DD: Inter- and intraclade neutralization of human immunodeficiency virus type 1: genetic clades do not correspond to neutralization serotypes but partially correspond to gp120 antigenic serotypes.

Desrosiers RC: Envelope sequence variation, neutralizing antibodies and primate lentivirus persistence. Curr Top Microbiol Immunol

Does the key to a successful HIV vaccine lie among the envelope sequences of infected individuals? Aids Res Hum Retroviruses

Edubio A, et al.: Molecular surveillance of HIV-1 field strains in Nigeria in preparation for vaccine trials. Vaccine

et al.: HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature

et al.: Human immunodeficiency virus type 1 superinfection was not detected following 215 years of injection drug user exposure.

et al.: Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation.

et al.: Long lived multi-isotype anti-HIV antibody responses following a prime-double boost immunization strategy. Vaccine

Human immunodeficiency virus type 1 subtype C molecular phylogeny: consensus sequence for an AIDS vaccine design?

Immunoreactivity of intact virions of human immunodeficiency virus type 1 (HIV-1) reveals the existence of fewer HIV-1 immunotypes than genotypes.

JL: Minor components of a multi-envelope HIV vaccine are recognized by type-specific T-helper cells. Vaccine

JL: Structural features of HIV envelope defined by antibody escape mutant analysis. AIDS Res Hum Retroviruses

Limited breadth of a T-helper cell response to a human immunodeficiency virus envelope protein.

Live attenuated simian immunodeficiency virus prevents superinfection by cloned SIVmac251 in cynomolgus monkeys.

Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy. Lancet Infect Dis

MP: Two percent of HIV-positive U.S. blood donors are infected with non-subtype B strains. AIDS Res Hum Retroviruses

Poliomyelitis in the light of recent experimental work. Health Bulletin. Department of Health-Victoria,

Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies – implications for acquired immunodeficiency syndrome vaccine. J Infect Dis

Precise mapping of recombination breakpoints suggests a common parent of two BC recombinant HIV type 1 strains circulating in China. AIDS Res Hum Retroviruses

RC: Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science

Subcutaneous administration of a recombinant vaccinia virus vaccine expressing multiple envelopes of HIV-1.

Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E. J Virol

Travel and the spread of HIV-1 genetic variants. Lancet Infect Dis

Varicella disease after introduction of varicella vaccine in the United States,

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1112584

Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?

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