Skip to main content

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


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 subsequent travel of infected persons and the continued practice of high-risk behaviors fostered virus transmission to virtually every world region. Once HIV-1 awareness was heightened and HIV-1 sequencing projects were implemented, regional similarities of viral sequences, presumably 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 continuous virus transmission, mutation and recombination, the demarcation of HIV-1 subtypes has become increasingly blurred, and the categorization of viruses by clade is increasingly difficult [25]. Nonetheless scientists are currently encouraged to custom-design vaccines based on a particular country or clade [611]. To this end, a single viral sequence may be selected, possibly based on a formula of ancestry or consensus, to represent all other viruses in the targeted category.

Designing vaccines in this way prompts careful consideration: 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 vaccines be produced? Who will decide? The complexity of such 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 necessary.

Do immune responses discriminate between clades?

While differences in encoded protein sequence may permit discrimination between certain HIV-1 subtypes, successful 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 [1214]. 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 structures bound by antibodies can occur on proteins that differ 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 targets. Conversely, two viruses may have 99% sequence similarity, yet a particular neutralizing antibody or T-cell receptor may discriminate between them. This discrimination 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 sequestration in "privileged" sites, hidden from the immune system), most individuals are resistant to super-infection [1722]. 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 vaccine 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 function 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 [2830]. 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 infections in every world region, and to overcome the political and financial dilemmas associated with the production of clade, country or region-specific vaccines.


  1. Perrin L, Kaiser L, Yerly S: Travel and the spread of HIV-1 genetic variants. Lancet Infect Dis. 2003, 3: 22-27. 10.1016/S1473-3099(03)00484-5

    Article  PubMed  Google Scholar 

  2. Delwart EL, Orton S, Parekh B, Dobbs T, Clark K, Busch MP: Two percent of HIV-positive U.S. blood donors are infected with non-subtype B strains. AIDS Res Hum Retroviruses. 2003, 19 (12): 1065-1070. 10.1089/088922203771881149

    Article  CAS  PubMed  Google Scholar 

  3. Anderson JP, Rodrigo AG, Learn GH, Madan A, Delahunty C, Coon M: Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E. J Virol. 2000, 74 (22): 10752-10765. 10.1128/JVI.74.22.10752-10765.2000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. McClutchan FE, Carr JK, Murphy D, Piyasirisilp S, Gao F, Hahn B: Precise mapping of recombination breakpoints suggests a common parent of two BC recombinant HIV type 1 strains circulating in China. AIDS Res Hum Retroviruses. 2002, 18 (15): 1135-1140. 10.1089/088922202320567879

    Article  CAS  PubMed  Google Scholar 

  5. Thomson MM, Perez-Alvarez L, Najera R: Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy. Lancet Infect Dis. 2002, 2 (8): 461-471. 10.1016/S1473-3099(02)00343-2

    Article  CAS  PubMed  Google Scholar 

  6. Williamson C, Morris L, Maughan MF, Ping LH, Dryga SA, Thomas R: Characterization and selection of HIV-1 subtype C isolates for use in vaccine development. AIDS Res Hum Retroviruses. 2003, 19 (2): 133-144. 10.1089/088922203762688649

    Article  CAS  PubMed  Google Scholar 

  7. Gaschen B, Taylor J, Yusim K, Foley B, Gao F, Lang D: Diversity considerations in HIV-1 vaccine selection. Science. 2002, 296 (5577): 2354-2360. 10.1126/science.1070441

    Article  CAS  PubMed  Google Scholar 

  8. Hanke T, Barnfield C, Wee EG, Agren L, Samuel RV, Larke N: Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine. J Gen Virol. 2003, 84: 361-368. 10.1099/vir.0.18738-0

    Article  CAS  PubMed  Google Scholar 

  9. Novitsky V, Smith UR, Gilbert P, McLane MF, Chigwedere P, Williamson C: Human immunodeficiency virus type 1 subtype C molecular phylogeny: consensus sequence for an AIDS vaccine design?. J Virol. 2002, 76: 5435-5451. 10.1128/JVI.76.11.5435-5451.2002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Hanke T, McMichael AJ: Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nature Medicine. 2000, 6: 951-955. 10.1038/79626

    Article  CAS  PubMed  Google Scholar 

  11. Agwale SM, Zeh C, Robbins KE, Odama L, Saekhou A, Edubio A: Molecular surveillance of HIV-1 field strains in Nigeria in preparation for vaccine trials. Vaccine. 2002, 20 (2131): 2139-

    Google Scholar 

  12. Cao H, Mani I, Vincent R, Mugerwa R, Mugyenyi P, Kanki P: Cellular immunity to human immunodeficiency virus type 1 (HIV-1) clades: relevance to HIV-1 vaccine trials in Uganda. J Infect Dis. 2000, 182: 1350-1356. 10.1086/315868

    Article  CAS  PubMed  Google Scholar 

  13. Moore JP, Cao Y, Leu J, Qin L, Korber B, Ho 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. J Virol. 1996, 70: 427-444.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Ferrantelli F, Kitabwalla M, Rasmussen RA, Cao C, Chou TC, Katinger H: Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies – implications for acquired immunodeficiency syndrome vaccine. J Infect Dis. 2004, 189: 71-74. 10.1086/420833

    Article  PubMed  Google Scholar 

  15. D'Costa S, Slobod KS, Webster RG, White SW, Hurwitz JL: Structural features of HIV envelope defined by antibody escape mutant analysis. AIDS Res Hum Retroviruses. 2001, 17: 1205-1209. 10.1089/088922201316912808

    Article  PubMed  Google Scholar 

  16. Zhan X, Slobod KS, Surman S, Brown SA, Lockey TD, Coleclough C: Limited breadth of a T-helper cell response to a human immunodeficiency virus envelope protein. J Virol. 2003, 77: 4231-4236. 10.1128/JVI.77.7.4231-4236.2003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Gonzales MJ, Delwart E, Rhee SY, Tsui R, Zolopa AR, Taylor J: Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation. J Infect Dis. 2003, 188: 397-405. 10.1086/376534

    Article  PubMed Central  PubMed  Google Scholar 

  18. Tsui R, Herring BL, Barbour JD, Grant RM, Bacchetti P, Kral A: Human immunodeficiency virus type 1 superinfection was not detected following 215 years of injection drug user exposure. J Virol. 2004, 78: 94-103. 10.1128/JVI.78.1.94-103.2004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Altfeld M, Allen TM, Yu XG, Johnston MN, Agrawal D, Korber BT: HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature. 2002, 420: 434-439. 10.1038/nature01200

    Article  CAS  PubMed  Google Scholar 

  20. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC: Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science. 1992, 258: 1938-1941.

    Article  CAS  PubMed  Google Scholar 

  21. Burns DPW, Desrosiers RC: Envelope sequence variation, neutralizing antibodies and primate lentivirus persistence. Curr Top Microbiol Immunol. 1994, 188: 185-219.

    CAS  PubMed  Google Scholar 

  22. Titti F, Sernicola L, Geraci A, Panzini G, Di Fabio S, Belli R: Live attenuated simian immunodeficiency virus prevents super-infection by cloned SIVmac251 in cynomolgus monkeys. J Gen Virol. 1997, 78: 2529-2539.

    Article  CAS  PubMed  Google Scholar 

  23. Wrin T, Crawford L, Sawyer L, Weber P, Sheppard HW, Hanson CV: Neutralizing antibody responses to autologous and heterologous isolates of human immunodeficiency virus. J Acquir Immune Defic Syndr. 1994, 7: 211-219.

    CAS  PubMed  Google Scholar 

  24. Richman DD, Wrin T, Little SJ, Petropoulos CJ: Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A. 2003, 100 (7): 4144-4149. 10.1073/pnas.0630530100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Rencher SD, Slobod KS, Dawson D, Lockey TD, Hurwitz JL: Does the key to a successful HIV vaccine lie among the envelope sequences of infected individuals?. Aids Res Hum Retroviruses. 1995, 11: 1131-1133.

    Article  CAS  PubMed  Google Scholar 

  26. Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX: Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. JAMA. 2002, 287 (5): 606-611. 10.1001/jama.287.5.606

    Article  PubMed  Google Scholar 

  27. Nyambi PN, Nadas A, Mbah HA, Burda S, Williams C, Gorny MK: Immunoreactivity of intact virions of human immunodeficiency virus type 1 (HIV-1) reveals the existence of fewer HIV-1 immunotypes than genotypes. J Virol. 2000, 74 (22): 10670-10680. 10.1128/JVI.74.22.10670-10680.2000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Slobod KS, Lockey TD, Howlett N, Srinivas RV, Rencher SD, Freiden PJ: Subcutaneous administration of a recombinant vaccinia virus vaccine expressing multiple envelopes of HIV-1. Eur J Clin Microbiol Infect Dis. 2004, 23: 106-110. 10.1007/s10096-003-1075-3

    Article  CAS  PubMed  Google Scholar 

  29. Hurwitz JL, Slobod KS, Lockey TD, Wang S, Chou T-HW, Lu S: Application of the polyvalent approach to HIV-1 vaccine development. Current Drug Targets-Infectious Disorders. 2005

    Google Scholar 

  30. Stambas J, Brown SA, Gutierrez A, Sealy R, Yue W, Jones B: Long lived multi-isotype anti-HIV antibody responses following a prime-double boost immunization strategy. Vaccine. 2005, 23: 2454-2464. 10.1016/j.vaccine.2004.10.030

    Article  CAS  PubMed  Google Scholar 

  31. Zhan X, Slobod KS, Surman S, Brown SA, Coleclough C, Hurwitz JL: Minor components of a multi-envelope HIV vaccine are recognized by type-specific T-helper cells. Vaccine. 2004, 22: 1206-1213. 10.1016/j.vaccine.2003.09.028

    Article  CAS  PubMed  Google Scholar 

  32. Burnet FM: Poliomyelitis in the light of recent experimental work. Health Bulletin. Department of Health-Victoria, Australia. 1945

    Google Scholar 

Download references


This work was supported in part by NIH NIAID P01-AI45142, NCI Cancer Center Support Core Grant P30-CA21765, the Mitchell Fund, the Federated Department Stores, the James B. Pendleton Charitable Trust and the American Lebanese Syrian associated Charities (ALSAC).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Julia L Hurwitz.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Slobod, K.S., Coleclough, C., Brown, S.A. et al. Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?. AIDS Res Ther 2, 3 (2005).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: