B-cell epitope prediction aims to aid the design of peptide-based immunogens (e.g., vaccines) for eliciting antipeptide antibodies that protect against disease, but such antibodies fail to confer protection and even promote disease if they bind with low affinity. Hence, the Immune Epitope Database (IEDB) was searched to obtain published thermodynamic and kinetic data on binding interactions of antipeptide antibodies. The data suggest that the affinity of the antibodies for their immunizing peptides appears to be limited in a manner consistent with previously proposed kinetic constraints on affinity maturation in vivo and that cross-reaction of the antibodies with proteins tends to occur with lower affinity than the corresponding reaction of the antibodies with their immunizing peptides. These observations better inform B-cell epitope prediction to avoid overestimating the affinity for both active and passive immunization; whereas active immunization is subject to limitations of affinity maturation in vivo and of the capacity to accumulate endogenous antibodies, passive immunization may transcend such limitations, possibly with the aid of artificial affinity-selection processes and of protein engineering. Additionally, protein disorder warrants further investigation as a possible supplementary criterion for B-cell epitope prediction, where such disorder obviates thermodynamically unfavorable protein structural adjustments in cross-reactions between antipeptide antibodies and proteins. 1. Introduction Antibody-mediated immunity is the basis of most conventional approaches to immunization, which protect against or treat disease by means of antibodies that are either endogenous (i.e., produced via active immunization, notably through the administration of vaccines that elicit antibody responses) or exogenous (i.e., acquired via passive immunization through the administration of preformed antibodies from some external source, such as a human or animal donor). Historically, these approaches have been developed and pursued mainly for the prevention and control of communicable infectious diseases viewed as public-health problems, which is ever more crucial to adequately address current and anticipated global-health challenges posed by emerging and reemerging pathogens that cause pandemics and panzootics (both of which may be inextricably linked in cases of zoonoses such as avian and swine influenza) [1]. Yet, the envisioned practical applications of antibody-mediated immunity increasingly include therapy for and prophylaxis against diseases such as cancer and
References
[1]
S. E. Caoili, “B-cell epitope prediction for peptide-based vaccine design: towards a paradigm of biological outcomes for global health,” Immunome Research, vol. 7, no. 2, article 2, 2011.
[2]
T. A. R？hn and M. F. Bachmann, “Vaccines against non-communicable diseases,” Current Opinion in Immunology, vol. 22, no. 3, pp. 391–396, 2010.
[3]
J. S？llner, “Beyond epitopes: future and application of computational vaccinology,” Human Vaccines, vol. 7, no. 7, pp. 795–797, 2011.
[4]
G. Eberl, “A new vision of immunity: homeostasis of the superorganism,” Mucosal Immunology, vol. 3, no. 5, pp. 450–460, 2010.
[5]
M. H. Van Regenmortel, “What is a B-cell epitope?” Methods in Molecular Biology, vol. 524, pp. 3–20, 2009.
[6]
Y. El-Manzalawy and V. Honavar, “Recent advances in B-cell epitope prediction methods,” Immunome Research, vol. 6, no. 2, article S2, 2010.
[7]
J. S？llner, A. Heinzel, G. Summer et al., “Concept and application of a computational vaccinology workflow,” Immunome Research, vol. 6, no. supplement 2, article S7, 2010.
[8]
J. S？llner, R. Grohmann, R. Rapberger, P. Perco, A. Lukas, and B. Mayer, “Analysis and prediction of protective continuous B-cell epitopes on pathogen proteins,” Immunome Research, vol. 4, article 1, 2008.
[9]
S. M. C. Tirado and K. J. Yoon, “Antibody-dependent enhancement of virus infection and disease,” Viral Immunology, vol. 16, no. 1, pp. 69–86, 2003.
[10]
A. Takada and Y. Kawaoka, “Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications,” Reviews in Medical Virology, vol. 13, no. 6, pp. 387–398, 2003.
[11]
Z. Beck, Z. Prohászka, and G. Füst, “Traitors of the immune system-Enhancing antibodies in HIV infection: their possible implication in HIV vaccine development,” Vaccine, vol. 26, no. 24, pp. 3078–3085, 2008.
[12]
H. Stoiber, “Complement, Fc receptors and antibodies: a Trojan horse in HIV infection?” Current Opinion in HIV and AIDS, vol. 4, no. 5, pp. 394–399, 2009.
[13]
T. C. Pierson and M. S. Diamond, “Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection,” Expert Reviews in Molecular Medicine, vol. 10, article e12, 2008.
[14]
M. S. Diamond, T. C. Pierson, and D. H. Fremont, “The structural immunology of antibody protection against West Nile virus,” Immunological Reviews, vol. 225, no. 1, pp. 212–225, 2008.
[15]
S. Mahalingam and B. A. Lidbury, “Antibody-dependent enhancement of infection: bacteria do it too,” Trends in Immunology, vol. 24, no. 9, pp. 465–467, 2003.
[16]
S. B. Halstead, S. Mahalingam, M. A. Marovich, S. Ubol, and D. M. Mosser, “Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes,” The Lancet Infectious Diseases, vol. 10, no. 10, pp. 712–722, 2010.
[17]
O. Lund, J. Hansen, E. Mosekilde, J. O. Nielsen, and J. E. S. Hansen, “A model of enhancement and inhibition of HIV infection of monocytes by antibodies against HIV,” Journal of Biological Physics, vol. 19, no. 2, pp. 133–145, 1993.
[18]
M. A. Gertz and R. A. Kyle, “Hyperviscosity syndrome,” Journal of Intensive Care Medicine, vol. 10, no. 3, pp. 128–141, 1995.
[19]
J. Foote and H. N. Eisen, “Kinetic and affinity limits on antibodies produced during immune responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 5, pp. 1254–1256, 1995.
[20]
J. Foote and H. N. Eisen, “Breaking the affinity ceiling for antibodies and T cell receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 10679–10681, 2000.
[21]
K. P. Murphy, “Predicting binding energetics from structure: looking beyond ,” Medicinal Research Reviews, vol. 19, no. 4, pp. 333–339, 1999.
[22]
S. P. Edgcomb and K. P. Murphy, “Structural energetics of protein folding and binding,” Current Opinion in Biotechnology, vol. 11, no. 1, pp. 62–66, 2000.
[23]
S. E. C. Caoili, “A structural-energetic basis for B-cell epitope prediction,” Protein and Peptide Letters, vol. 13, no. 7, pp. 743–751, 2006.
[24]
S. E. C. Caoili, “Immunization with peptide-protein conjugates: impact on benchmarking B-cell epitope prediction for vaccine design,” Protein and Peptide Letters, vol. 17, no. 3, pp. 386–398, 2010.
[25]
C. J. van Oss, “Kinetics and energetics of specific intermolecular interactions,” Journal of Molecular Recognition, vol. 10, no. 5, pp. 203–216, 1997.
[26]
S. H. Northrup and H. P. Erickson, “Kinetics of protein-protein association explained by Brownian dynamics computer simulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 8, pp. 3338–3342, 1992.
[27]
C. S. Raman, R. Jemmerson, B. T. Nall, and M. J. Allen, “Diffusion-limited rates for monoclonal antibody binding to cytochrome c,” Biochemistry, vol. 31, no. 42, pp. 10370–10379, 1992.
[28]
C. Watts and H. W. Davidson, “Endocytosis and recycling of specific antigen by human B cell lines,” EMBO Journal, vol. 7, no. 7, pp. 1937–1945, 1988.
[29]
K. V. S. Rao, “Selection in a T-dependent primary humoral response: new insights from polypeptide models,” Acta Pathologica, Microbiologica et Immunologica, vol. 107, no. 9, pp. 807–818, 1999.
[30]
S. E. C. Caoili, “Benchmarking B-cell epitope prediction for the design of peptide-based vaccines: problems and prospects,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 910524, 14 pages, 2010.
[31]
Q. Zhang, P. Wang, Y. Kim et al., “Immune epitope database analysis resource (IEDB-AR),” Nucleic Acids Research, vol. 36, pp. W513–518, 2008.
[32]
L. M. Silva-Flannery, M. Cabrera-Mora, J. Jiang, and A. Moreno, “Recombinant peptide replicates immunogenicity of synthetic linear peptide chimera for use as pre-erythrocytic stage malaria vaccine,” Microbes and Infection, vol. 11, no. 1, pp. 83–91, 2009.
[33]
S. Subramanian, A. A. Karande, and P. R. Adiga, “Helix stabilization in the C-terminal peptide of chicken riboflavin carrier protein enhances immunogenicity and prolongs contraceptive potential as an epitope-based vaccine in female rats,” Biochemical and Biophysical Research Communications, vol. 287, no. 1, pp. 236–243, 2001.
[34]
N. A. Verwey, R. Veerhuis, H. A. M. Twaalfhoven et al., “Quantification of amyloid-beta 40 in cerebrospinal fluid,” Journal of Immunological Methods, vol. 348, no. 1-2, pp. 57–66, 2009.
[35]
C. Zahnd, S. Spinelli, B. Luginbühl, P. Amstutz, C. Cambillau, and A. Plückthun, “Directed in vitro evolution and crystallographic analysis of a peptide-binding single chain antibody fragment (scFv) with low picomolar affinity,” Journal of Biological Chemistry, vol. 279, no. 18, pp. 18870–18877, 2004.
[36]
H. Cordes, A. L. Bergstr？m, J. Ohm, H. Laursen, and P. M. H. Heegaard, “Characterisation of new monoclonal antibodies reacting with prions from both human and animal brain tissues,” Journal of Immunological Methods, vol. 337, no. 2, pp. 106–120, 2008.
[37]
S. Subramanian, A. A. Karande, and P. R. Adiga, “Immunocontraceptive potential of major antigenic determinants of chicken riboflavin carrier protein in the female rat,” Vaccine, vol. 19, no. 9-10, pp. 1172–1179, 2000.
[38]
E. D. Day, G. A. Hashim, D. J. Ireland, and N. T. Potter, “Polyclonal antibodies to the encephalitogenic neighborhoods of myelin basic protein: singular affinity populations neutralized by specific synthetic peptide probes,” Journal of Neuroimmunology, vol. 13, no. 2, pp. 143–158, 1986.
[39]
J. L. Bret-Dibat, D. Zouaoui, O. Dery et al., “Antipeptide polyclonal antibodies that recognize a substance P-binding site in mammalian tissues: a biochemical and immunocytochemical study,” Journal of Neurochemistry, vol. 63, no. 1, pp. 333–343, 1994.
[40]
M. Esumi, Y. H. Zhou, T. Tanoue, T. Tomoguri, and I. Hayasaka, “In vivo and in vitro evidence that cross-reactive antibodies to C-terminus of hypervariable region 1 do not neutralize heterologous hepatitis C virus,” Vaccine, vol. 20, no. 25-26, pp. 3095–3103, 2002.
[41]
B. Chaba, P. Kumar, W. Haq, L. Sabhnani, and D. N. Rao, “Influence of immunoadjuvants and a promiscous T-cell determinant on the immunogenicity of RESA peptide antigen of P. falciparum,” International Journal of Immunopharmacology, vol. 20, no. 6, pp. 259–273, 1998.
[42]
I. Hilgert, P. Stolba, H. Kristofova et al., “A monoclonal antibody applicable for determination of C-peptide of human proinsulin by RIA,” Hybridoma, vol. 10, no. 3, pp. 379–386, 1991.
[43]
V. Tripathi, K. T. Chitralekha, A. R. Bakshi et al., “Inducing systemic and mucosal immune responses to B-T construct of F1 antigen of Yersinia pestis in microsphere delivery,” Vaccine, vol. 24, no. 16, pp. 3279–3289, 2006.
[44]
P. Kumar, S. Biswas, and D. N. Rao, “Potentiation of immune response against the RESA peptides of Plasmodium falciparum by incorporating a universal T-cell epitope (CS.T3) and an immunomodulator (polytuftsin), and delivery through liposomes,” Microbiology and Immunology, vol. 43, no. 6, pp. 567–576, 1999.
[45]
H. Hillen, S. Barghorn, A. Striebinger et al., “Generation and therapeutic efficacy of highly oligomer-specific β-amyloid antibodies,” Journal of Neuroscience, vol. 30, no. 31, pp. 10369–10379, 2010.
[46]
A. Nowakowski, C. Wang, D. B. Powers et al., “Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11346–11350, 2002.
[47]
R. Robert, M. P. Lefranc, A. Ghochikyan et al., “Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide,” Molecular Immunology, vol. 48, no. 1–3, pp. 59–72, 2010.
[48]
W. Liu and Y. H. Chen, “High epitope density in a single protein molecule significantly enhances antigenicity as well as immunogenecity: a novel strategy for modern vaccine development and a preliminary investigation about B cell discrimination of monomeric proteins,” European Journal of Immunology, vol. 35, no. 2, pp. 505–514, 2005.
[49]
D. J. van den Heuvel, R. P. H. Kooyman, J. W. Drijfhout, and G. W. Welling, “Synthetic peptides as receptors in affinity sensors: a feasibility study,” Analytical Biochemistry, vol. 215, no. 2, pp. 223–230, 1993.
[50]
C. Li and J. P. Allain, “Chimeric monoclonal antibodies to hypervariable region 1 of hepatitis C virus,” Journal of General Virology, vol. 86, no. 6, pp. 1709–1716, 2005.
[51]
M. Skok, E. Lykhmus, S. Bobrovnik et al., “Structure of epitopes recognized by the antibodies to α(181–192) peptides of neuronal nicotinic acetylcholine receptors: extrapolation to the structure of acetylcholine-binding domain,” Journal of Neuroimmunology, vol. 121, no. 1-2, pp. 59–66, 2001.
[52]
E. Hanan, S. A. Priola, and B. Solomon, “Antiaggregating antibody raised against human PrP 106–126 recognizes pathological and normal isoforms of the whole prion protein,” Cellular and Molecular Neurobiology, vol. 21, no. 6, pp. 693–703, 2001.
[53]
S. M. Taubenfeld, Y. Song, D. Sheng, E. L. Ball, and G. R. Matsueda, “A monoclonal antibody against a peptide sequence of fibrinogen gamma chain acts as an inhibitor of factor XIII-mediated crosslinking of human fibrin,” Thrombosis and Haemostasis, vol. 74, no. 3, pp. 923–927, 1995.
[54]
A. J. Sytkowski and J. W. Fisher, “Isolation and characterization of an anti-peptide monoclonal antibody to human erythropoietin,” Journal of Biological Chemistry, vol. 260, no. 27, pp. 14727–14731, 1985.
[55]
S. Subramanian, P. R. Adiga, and A. A. Karande, “Immunocontraceptive efficacy of synthetic peptides corresponding to major antigenic determinants of chicken riboflavin carrier protein in the female rats,” American Journal of Reproductive Immunology, vol. 44, no. 3, pp. 184–191, 2000.
[56]
A. Helg, M. S. Mueller, A. Joss et al., “Comparison of analytical methods for the evaluation of antibody responses against epitopes of polymorphic protein antigens,” Journal of Immunological Methods, vol. 276, no. 1-2, pp. 19–31, 2003.
[57]
L. Sabhnani, M. Manocha, K. Sridevi, D. Shashikiran, R. Rayanade, and D. N. Rao, “Developing subunit immunogens using B and T cell epitopes and their constructs derived from the F1 antigen of Yersinia pestis using novel delivery vehicles,” FEMS Immunology and Medical Microbiology, vol. 38, no. 3, pp. 215–229, 2003.
[58]
J. M. H. van den Elsen, L. M. A. van Unen, L. van Bloois et al., “Thermodynamic analysis of the interaction between a bactericidal antibody and a PorA epitope of Neisseria meningitidis,” Biochemistry, vol. 36, no. 41, pp. 12583–12591, 1997.
[59]
O. E. Obeid, C. M. Stanley, and M. W. Steward, “Immunological analysis of the protective responses to the chimeric synthetic peptide representing T- and B-cell epitopes from the fusion protein of measles virus,” Virus Research, vol. 42, no. 1-2, pp. 173–180, 1996.
[60]
E. D. Day and G. A. Hashim, “Affinity purification of two populations of antibodies against format determinants of synthetic myelin basic protein peptide S82 from S82-AH- and S82-CH-Sepharose 4B columns,” Neurochemical Research, vol. 9, no. 10, pp. 1453–1465, 1984.
[61]
R. Moreno, F. P？ltl-Frank, D. Stüber et al., “Rhoptry-associated protein 1-binding monoclonal antibody raised against a heterologous peptide sequence inhibits Plasmodium falciparum growth in vitro,” Infection and Immunity, vol. 69, no. 4, pp. 2558–2568, 2001.
[62]
M. K. Mustafa, A. Nabok, D. Parkinson, I. E. Tothill, F. Salam, and A. Tsargorodskaya, “Detection of β-amyloid peptide (1–16) and amyloid precursor protein (APP770) using spectroscopic ellipsometry and QCM techniques: a step forward towards Alzheimers disease diagnostics,” Biosensors and Bioelectronics, vol. 26, no. 4, pp. 1332–1336, 2010.
[63]
J. T. Downs, C. L. Lane, N. B. Nestor et al., “Analysis of collagenase-cleavage of type II collagen using a neoepitope ELISA,” Journal of Immunological Methods, vol. 247, no. 1-2, pp. 25–34, 2001.
[64]
B. E. Thomas, M. Manocha, W. Haq, T. Adak, C. R. Pillai, and D. N. Rao, “Modulation of the humoral response to repeat and non-repeat sequences of the circumsporozoite protein of Plasmodium vivax using novel adjuvant and delivery systems,” Annals of Tropical Medicine and Parasitology, vol. 95, no. 5, pp. 451–472, 2001.
[65]
M. Kaur, H. Chug, H. Singh et al., “Identification and characterization of immunodominant B-cell epitope of the C-terminus of protective antigen of Bacillus anthracis,” Molecular Immunology, vol. 46, no. 10, pp. 2107–2115, 2009.
[66]
A. R. Neurath, S. B. H. Kent, and N. Strick, “Specificity of antibodies elicited by a synthetic peptide having a sequence in common with a fragment of a virus protein, the hepatitis B surface antigen,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 24, pp. 7871–7875, 1982.
[67]
M. Ramakrishnan, K. K. Kandimalla, T. M. Wengenack, K. G. Howell, and J. F. Poduslo, “Surface plasmon resonance binding kinetics of Alzheimer's disease amyloid β peptide-capturing and plaque-binding monoclonal antibodies,” Biochemistry, vol. 48, no. 43, pp. 10405–10415, 2009.
[68]
Y. Song, S. M. Taubenfeld, D. Sheng, and G. R. Matsueda, “Characterization of a monoclonal antibody directed against the carboxyl-terminus of human factor XIII. An epitope exposed upon denaturation and conserved across species lines,” Thrombosis and Haemostasis, vol. 71, no. 1, pp. 62–67, 1994.
[69]
P. J. Cachia, D. J. Kao, and R. S. Hodges, “Synthetic peptide vaccine development: measurement of polyclonal antibody affinity and cross-reactivity using a new peptide capture and release system for surface plasmon resonance spectroscopy,” Journal of Molecular Recognition, vol. 17, no. 6, pp. 540–557, 2004.
[70]
G. Ofek, F. J. Guenaga, W. R. Schief et al., “Elicitation of structure-specific antibodies by epitope scaffolds,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 42, pp. 17880–17887, 2010.
[71]
C. Partidos, C. Stanley, and M. Steward, “The effect of orientation of epitopes on the immunogenicity of chimeric synthetic peptides representing measles virus protein sequences,” Molecular Immunology, vol. 29, no. 5, pp. 651–658, 1992.
[72]
M. W. Steward, C. M. Stanley, R. Dimarchi, G. Mulcahy, and T. R. Doel, “High-affinity antibody induced by immunization with a synthetic peptide is associated with protection of cattle against foot-and-mouth disease,” Immunology, vol. 72, no. 1, pp. 99–103, 1991.
[73]
J. Anglister, C. Jacob, O. Assulin, G. Ast, R. Pinker, and R. Arnon, “NMR study of the complexes between a synthetic peptide derived from the B subunit of cholera toxin and three monoclonal antibodies against it,” Biochemistry, vol. 27, no. 2, pp. 717–724, 1988.
[74]
D. T. Nair, K. Singh, N. Sahu, K. V. S. Rao, and D. M. Salunke, “Crystal structure of an antibody bound to an immunodominant peptide epitope: novel features in peptide-antibody recognition,” Journal of Immunology, vol. 165, no. 12, pp. 6949–6955, 2000.
[75]
M. García, M. A. Alsina, F. Reig, and I. Haro, “Liposomes as vehicles for the presentation of a synthetic peptide containing an epitope of hepatitis A virus,” Vaccine, vol. 18, no. 3-4, pp. 276–283, 1999.
[76]
G. Zeder-Lutz, D. Altschuh, H. M. Geysen, E. Trifilieff, G. Sommermeyer, and M. H. V. Van Regenmortel, “Monoclonal antipeptide antibodies: affinity and kinetic rate constants measured for the peptide and the cognate protein using a biosensor technology,” Molecular Immunology, vol. 30, no. 2, pp. 145–155, 1993.
[77]
R. Vita, B. Peters, and A. Sette, “The curation guidelines of the immune epitope database and analysis resource,” Cytometry Part A, vol. 73, no. 11, pp. 1066–1070, 2008.
[78]
U. Hobohm, M. Scharf, R. Schneider, and C. Sander, “Selection of representative protein data sets,” Protein Science, vol. 1, no. 3, pp. 409–417, 1992.
[79]
U. Lessel and D. Schomburg, “Creation and characterization of a new, non-redundant fragment data bank,” Protein Engineering, vol. 10, no. 6, pp. 659–664, 1997.
[80]
T. Noguchi and Y. Akiyama, “PDB-REPRDB: a database of representative protein chains from the Protein Data Bank (PDB) in 2003,” Nucleic Acids Research, vol. 31, no. 1, pp. 492–493, 2003.
[81]
P. Motte, G. Alberici, M. Ait-Abdellah, and D. Bellet, “Monoclonal antibodies distinguish synthetic peptides that differ in one chemical group,” Journal of Immunology, vol. 138, no. 10, pp. 3332–3338, 1987.
[82]
E. Nardin, “The past decade in malaria synthetic peptide vaccine clinical trials,” Human Vaccines, vol. 6, no. 1, pp. 27–38, 2010.
[83]
S. W. W. Chen, M. H. V. Van Regenmortel, and J. L. Pellequer, “Structure-activity relationships in peptide-antibody complexes: implications for epitope prediction and development of synthetic peptide vaccines,” Current Medicinal Chemistry, vol. 16, no. 8, pp. 953–964, 2009.
[84]
G. Nudelman and Y. Louzoun, “Cell surface dynamics: the balance between diffusion, aggregation and endocytosis,” IEE Proceedings Systems Biology, vol. 153, no. 1, pp. 34–42, 2006.
[85]
G. Nudelman, M. Weigert, and Y. Louzoun, “In-silico cell surface modeling reveals mechanism for initial steps of B-cell receptor signal transduction,” Molecular Immunology, vol. 46, no. 15, pp. 3141–3150, 2009.
[86]
A. K. Dunker, C. J. Brown, J. D. Lawson, L. M. Iakoucheva, and Z. Obradovi？, “Intrinsic disorder and protein function,” Biochemistry, vol. 41, no. 21, pp. 6573–6582, 2002.
[87]
J. L. Pellequer, E. Westhof, and M. H. V. Van Regenmortel, “Correlation between the location of antigenic sites and the prediction of turns in proteins,” Immunology Letters, vol. 36, no. 1, pp. 83–99, 1993.
[88]
G. D. Rose, L. M. Glerasch, and J. A. Smith, “Turns in Peptides and Proteins,” Advances in Protein Chemistry, vol. 37, pp. 1–109, 1985.
[89]
H. J. Dyson, R. A. Lerner, and P. E. Wright, “The physical basis for induction of protein-reactive antipeptide antibodies,” Annual Review of Biophysics and Biophysical Chemistry, vol. 17, pp. 305–324, 1988.
[90]
S. A. Plotkin, “Correlates of protection induced by vaccination,” Clinical and Vaccine Immunology, vol. 17, no. 7, pp. 1055–1065, 2010.
[91]
M. H. Van Regenmortel, “Basic research in HIV vaccinology is hampered by reductionist thinking,” Frontiers in Immunology, vol. 3, article 194, 2012.
[92]
S. S. Coughlin, “How many principles for public health ethics?” Open Public Health Journal, vol. 1, pp. 8–16, 2008.
[93]
E. J. Emanuel and A. Wertheimer, “Who should get influenza vaccine when not all can?” Science, vol. 312, no. 5775, pp. 854–855, 2006.
[94]
A. P. Galvani, T. C. Reluga, and G. B. Chapman, “Long-standing influenza vaccination policy is in accord with individual self-interest but not with the utilitarian optimum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 13, pp. 5692–5697, 2007.
