Search tips
Search criteria 


Logo of f1000bioLatest ContentReportsReportsReports
F1000 Biol Rep. 2010; 2: 60.
Published online 2010 August 9. doi:  10.3410/B2-60
PMCID: PMC2990654

New templates for HIV-1 antibody-based vaccine design


A current strategy for the design of neutralizing antibody-based vaccines to prevent HIV-1 transmission is that of reverse engineering, starting from a neutralizing antibody and working back to reconstruct its epitope by structure-based design technology. However, the field has been impeded by a lack of appropriate antibodies for use as templates. Recently, new antibodies have been described that may fulfil this role, invigorating the field.

Introduction and context

The human immunodeficiency virus type-1 (HIV-1) is the cause of AIDS and responsible for a major global pandemic, with an estimated 33 million people infected. The most cost-effective mechanism of infectious disease control is vaccination, but to date we have seen only modest success at reducing HIV-1 transmission in a single vaccine efficacy trial [1].

Of the two effector arms of the adaptive immune system involved in vaccine-mediated protection against infectious disease (cytotoxic T cell and antibody), antibodies are most likely to be effective in preventing HIV-1 infection [2-4]. The only target of neutralizing antibodies (NAbs) on HIV-1 is the virally encoded Env glycoprotein. Env is a trimer of heterodimers, each of which is composed of a receptor-binding surface glycoprotein (gp120) and a fusogenic transmembrane glycoprotein (gp41), linked together by non-covalent bonds (Figure 1a) [5]. The majority of Env is cloaked in carbohydrate (Figure 1b) and is highly variable (a) in terms of amino acid sequence between individual virus strains and (b) within an individual virus in terms of Env tertiary and quaternary conformational flexibility [6,7]. These potent immune evasion strategies mean that most NAbs will bind to only a few strains of virus and frequently only with low avidity.

Figure 1.
Location of BNMAb epitopes on HIV-1 Env

A recent concept is that of using NAbs as templates for recreation of their epitopes in a context different from that of the natural antigen [7-9]. For example, the sequence of a linear epitope can be used to design synthetic peptides that may induce the same specificity of antibody when used as an immunogen. Unfortunately, all linear NAb epitopes discovered to date in Env, excluding some binding within the membrane-proximal external region (MPER) of gp41 (see below), are highly variable and so induce only antibodies that neutralize a narrow range of viral strains. But neutralizing monoclonal antibodies (NMAbs) that recognize conformation-dependent epitopes and that neutralize a wide spectrum of viral strains exist, and these are under development as templates for vaccine antigen design. Until this past year, four NAbs of human origin had dominated the field: IgG1b12, a recombinant NAb derived from a phage-display library that recognizes the CD4-binding site (CD4bs) on gp120; 2G12, an NMAb binding a glycan epitope on gp120; and 2F5 and 4E10, two NMAbs binding the MPER of gp41 (Figure 1) [2,6,7]. Although the epitopes of all of these antibodies are defined and have been excellent prototypes for studying breadth of neutralization, each of these NMAbs has specific difficulties that so far have prevented its successful use as an antigen design template (for details, see [7,8]). Moreover, it is unclear whether these antibodies represent rare or even unique events in B-cell clonal selection or affinity maturation (or both). A related question is whether the relatively rare HIV-1-infected individuals with high-potency, broad-spectrum neutralizing antisera make individual NAbs with specificities that target highly conserved surfaces on Env or whether the neutralization breadth and potency of their sera are predominantly the sum of multiple responses each directed against a strain-specific epitope. We now have answers to these questions in the form of an analysis of the specificities of neutralization in high-titer antisera and several new NMAbs of unusual breadth and potency.

Major recent advances

The availability of high-throughput neutralization assays containing chimeric viruses expressing panels of Env cloned from diverse HIV-1 strains has allowed estimates of the proportion of HIV-1-infected individuals with substantial breadth and titer of serum neutralization [10]. This figure approaches 25% of chronically infected individuals [11-13], raising hope that such responses could be elicited by vaccination in a sizeable proportion of the general population. Strategies based mainly upon affinity trapping of distinct antibody specificities followed by functional analysis of neutralization have allowed mapping of the serum NAb response to HIV-1 with improved resolution and have revealed that the CD4bs is an important target of broadly neutralizing antibody (BNAb) [14,15]. Other regions targeted more rarely by BNAb are the gp41 MPER and the coreceptor-binding region [12]. Several of the studies found multiple NAb specificities, some of which were not accounted for by the known BNAb epitopes, implying novel conserved targets [15-17]. Representatives of such novel specificities were recently reported by Walker and colleagues [18] in the form of two related broadly neutralizing monoclonal antibodies (BNMAbs) (PG9 and PG16) that neutralized approximately 80-90% of representative HIV-1 strains with potencies approximately 10-fold greater than those of the previous BNMAbs. These BNMAbs were cloned from B cells of an HIV-1-infected individual with unusual breadth of serum neutralization activity and were found to bind complex discontinuous epitopes present only on the functional Env structure [18] (Figure 1a). Currently, it is unclear whether these BNMAbs bind epitopes that span more than one protomer within the trimer or whether they bind individual protomers that require a trimeric context to present the epitope. In either case, the quaternary structure dependency of the epitope will present particular challenges for antigen design. Another study found a new BNMAb (HJ16) reactive with an epitope within the CD4bs which is distinct from IgG1b12 but neutralizes a similar proportion (30-40%) of strains [19]. The epitope appears to be robustly expressed on monomeric gp120 under various conditions, suggesting that it may be amenable to structure-based reiteration. Finally, using a new structure-based strategy for selecting CD4bs-specific B cells, a very recent study reports on the isolation of antibodies (VRC01 and VRC02) that neutralize up to 90% of circulating strains of virus at low concentration [20]. At present, the structure of these BNMAb epitopes is unknown, but such potent and broad neutralizing activity in HIV-1-infected individuals gives hope that vaccine antigens based upon one or a few epitopes may be sufficient to protect the majority of the population from infection.

Future directions

The concept of structure-based vaccine design relies on the elucidation of the atomic structure of the target epitope, and this is under way for the recently isolated BNMAbs described above. The translation of structures into antigens for re-eliciting such NAb specificities is a major hurdle since the field has yet to demonstrate proof of principle for this concept. Antibody epitopes that are continuous or conformationally stable (or both) will be the easiest to mimic, and since epitope discovery is largely empiric, it will be important to isolate as many BNMAbs as possible to improve the chances of success in the design of antigens. Once antigens that re-elicit the desired antibody specificities are available, the next challenges to overcome will be those of B- cell immunodominance and of increasing the magnitude and persistence of the B-cell response to vaccination. Not enough is known of the mechanisms underlying these factors, but much will depend upon the adjuvants used to deliver robust T-cell help, B-cell activation, and subsequent affinity maturation and the long-term persistence of antibody-producing plasma cells at the appropriate anatomical locations. Research into all of these areas should be carried out in parallel as a high priority.


We thank Bill Schief for use of the Env model in Figure 1. QJS is a Jenner Institute Investigator. AM is supported by the National Institute of Allergy and Infectious Disease (NIAID) Center for HIV/AIDS Vaccine Immunology (CHAVI) funding (A1067854-03).


broadly neutralizing antibody
broadly neutralizing monoclonal antibody
human immunodeficiency virus type-1 envelope glycoprotein
human immunodeficiency virus type-1
membrane-proximal external region
neutralizing antibody
neutralizing monoclonal antibody


The electronic version of this article is the complete one and can be found at:


Competing Interests

The authors declare that they have no competing interests.


1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–20. doi: 10.1056/NEJMoa0908492. [PubMed] [Cross Ref] F1000 Factor 9.6 Exceptional
Evaluated by Barney Graham 26 Oct 2009, Rino Rappuoli 03 Nov 2009
2. Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Annu Rev Immunol. 2010;28:413–44. doi: 10.1146/annurev-immunol-030409-101256. [PubMed] [Cross Ref]
3. McMichael AJ. HIV vaccines. Annu Rev Immunol. 2006;24:227–55. doi: 10.1146/annurev.immunol.24.021605.090605. [PubMed] [Cross Ref]
4. Walker BD, Burton DR. Toward an AIDS vaccine. Science. 2008;320:760–4. doi: 10.1126/science.1152622. [PubMed] [Cross Ref]
5. Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science. 1998;280:1884–8. doi: 10.1126/science.280.5371.1884. [PubMed] [Cross Ref]
6. Pantophlet R, Burton DR. GP120: target for neutralizing HIV-1 antibodies. Annu Rev Immunol. 2006;24:739–69. doi: 10.1146/annurev.immunol.24.021605.090557. [PubMed] [Cross Ref]
7. Schief WR, Ban YE, Stamatatos L. Challenges for structure-based HIV vaccine design. Curr Opin HIV AIDS. 2009;4:431–40. doi: 10.1097/COH.0b013e32832e6184. [PubMed] [Cross Ref]
8. Walker LM, Burton DR. Rational antibody-based HIV-1 vaccine design: current approaches and future directions. Curr Opin Immunol. 2010;22:358–66. doi: 10.1016/j.coi.2010.02.012. [PMC free article] [PubMed] [Cross Ref]
9. Burton DR. Antibodies, viruses and vaccines. Nat Rev Immunol. 2002;2:706–13. doi: 10.1038/nri891. [PubMed] [Cross Ref]
10. Li M, Gao F, Mascola JR, Stamatatos L, Polonis VR, Koutsoukos M, Voss G, Goepfert P, Gilbert P, Greene KM, Bilska M, Kothe DL, Salazar-Gonzalez JF, Wei X, Decker JM, Hahn BH, Montefiori DC. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol. 2005;79:10108–25. doi: 10.1128/JVI.79.16.10108-10125.2005. [PMC free article] [PubMed] [Cross Ref]
11. Doria-Rose NA, Klein RM, Manion MM, O’Dell S, Phogat A, Chakrabarti B, Hallahan CW, Migueles SA, Wrammert J, Ahmed R, Nason M, Wyatt RT, Mascola JR, Connors M. Frequency and phenotype of human immunodeficiency virus envelope-specific B cells from patients with broadly cross-neutralizing antibodies. J Virol. 2009;83:188–99. doi: 10.1128/JVI.01583-08. [PMC free article] [PubMed] [Cross Ref]
12. Sather DN, Armann J, Ching LK, Mavrantoni A, Sellhorn G, Caldwell Z, Yu X, Wood B, Self S, Kalams S, Stamatatos L. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J Virol. 2009;83:757–69. doi: 10.1128/JVI.02036-08. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Gabriella Scarlatti 09 Feb 2009
13. Simek MD, Rida W, Priddy FH, Pung P, Carrow E, Laufer DS, Lehrman JK, Boaz M, Tarragona-Fiol T, Miiro G, Birungi J, Pozniak A, McPhee DA, Manigart O, Karita E, Inwoley A, Jaoko W, Dehovitz J, Bekker LG, Pitisuttithum P, Paris R, Walker LM, Poignard P, Wrin T, Fast PE, Burton DR, Koff WC. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J Virol. 2009;83:7337–48. doi: 10.1128/JVI.00110-09. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Eric Hunter 12 Aug 2009
14. Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, Wu X, Shaw GM, Connors M, Wyatt RT, Mascola JR. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med. 2007;13:1032–4. doi: 10.1038/nm1624. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Luigi Buonaguro 11 Oct 2007
15. Li Y, Svehla K, Louder MK, Wycuff D, Phogat S, Tang M, Migueles SA, Wu X, Phogat A, Shaw GM, Connors M, Hoxie J, Mascola JR, Wyatt R. Analysis of neutralization specificities in polyclonal sera derived from human immunodeficiency virus type 1-infected individuals. J Virol. 2009;83:1045–59. doi: 10.1128/JVI.01992-08. [PMC free article] [PubMed] [Cross Ref]
16. Gray ES, Taylor N, Wycuff D, Moore PL, Tomaras GD, Wibmer CK, Puren A, DeCamp A, Gilbert PB, Wood B, Montefiori DC, Binley JM, Shaw GM, Haynes BF, Mascola JR, Morris L. Antibody specificities associated with neutralization breadth in plasma from human immunodeficiency virus type 1 subtype C-infected blood donors. J Virol. 2009;83:8925–37. doi: 10.1128/JVI.00758-09. [PMC free article] [PubMed] [Cross Ref]
17. Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, Decker JM, Wycuff D, Harris L, Hawkins N, Wood B, Nathe C, Richman D, Tomaras GD, Bibollet-Ruche F, Robinson JE, Morris L, Shaw GM, Montefiori DC, Mascola JR. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. J Virol. 2008;82:11651–68. doi: 10.1128/JVI.01762-08. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Leo Stamatatos 08 Oct 2008
18. Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW, Protocol G Principal Investigators. Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DR. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science. 2009;326:285–9. doi: 10.1126/science.1178746. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 9.8 Exceptional
Evaluated by Rino Rappuoli 11 Sep 2009, James Crowe 23 Sep 2009, Moriya Tsuji 17 Dec 2009
19. Corti D, Langedijk JP, Hinz A, Seaman MS, Vanzetta F, Fernandez-Rodriguez BM, Silacci C, Pinna D, Jarrossay D, Balla-Jhagjhoorsingh S, Willems B, Zekveld MJ, Dreja H, O’Sullivan E, Pade C, Orkin C, Jeffs SA, Montefiori DC, Davis D, Weissenhorn W, McKnight A, Heeney JL, Sallusto F, Sattentau QJ, Weiss RA, Lanzavecchia A. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One. 2010;5:e8805. doi: 10.1371/journal.pone.0008805. [PMC free article] [PubMed] [Cross Ref]
20. Wu X, Yang Z-Y, Li Y, Hogerkorp C-M, Schief W, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo N, McKee K, O’Dell S, Louder MK, Wycuff D, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010 doi: 10.4016/18653.01. in press. [PMC free article] [PubMed] [Cross Ref]
21. Liu J, Bartesaghi A, Borgnia MJ, Sapiro G, Subramaniam S. Molecular architecture of native HIV-1 gp120 trimers. Nature. 2008;455:109–13. doi: 10.1038/nature07159. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6.4 Must Read
Evaluated by James K Stoops 11 Aug 2008, Tony Crowther 18 Sep 2008
22. Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 2007;445:732–7. doi: 10.1038/nature05580. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 8.0 Exceptional
Evaluated by Patricia C Weber 06 Mar 2007, Rino Rappuoli 07 Mar 2007

Articles from F1000 Biology Reports are provided here courtesy of Faculty of 1000 Ltd