- Email: [email protected]
Immunological correlates of protection for the RTS,S candidate malaria vaccine
Comment
immune responses induced by the two vaccines compare is unknown. The ultimate question that remains is whether higher antibody responses as recorded in the study by Nicholson and colleagues translate into superior protection. Comparison of vaccine effectiveness data in countries where different H1N1 pandemic vaccines have been used side by side in comparable populations will hopefully shed some light on this important issue.
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*Geert Leroux-Roels, Isabel Leroux-Roels Centre for Vaccinology, Ghent University and Hospital, Ghent, Belgium [email protected] GL-R has received payment as a consultant, for lectures, and to cover travel and accommodation from GSK Biologicals and has received payment as a consultant from Novartis Vaccines and Diagnostics. IL-R has received payment for a lecture and to cover travel and accommodation from GSK Biologicals and has received payment for a lecture from Sanofi Pasteur. 1
2 3
Nicholson KG, Abrams KR, Batham S, et al. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-tohead trial. Lancet Infect Dis 2010; published online Dec 17. DOI:10.1016/S1473-3099(10)70296-6. Stephenson I, Heath A, Major D, et al. Reproducibility of serologic assays for influenza virus A (H5N1). Emerg Infect Dis 2009; 15: 1252–59. Waddington CS, Walker WT, Oeser C, et al. Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months–12 years: open label, randomised, parallel group, multicentre study. BMJ 2010; 340: c2649.
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Waddington C, Andrews N, Hoschler K, et al. Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03B/oil-in-water emulsion-adjuvanted (AS03B) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. Health Technol Assess 2010; 14: 1–130. Leroux-Roels I, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370: 580–89. Rumke HC, Bayas JM, de Juanes JR, et al. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine 2008; 26: 2378–88. Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Devaster JM. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine 2010; 28: 1740–45. Clark TW, Pareek M, Hoschler K, et al. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med 2009; 361: 2424–35. Girard MP, Katz J, Pervikov Y, Palkonyay L, Kieny MP. Report of the 6th meeting on the evaluation of pandemic influenza vaccines in clinical trials World Health Organization, Geneva, Switzerland, 17–18 February 2010. Vaccine 2010; 28: 6811–20. Leroux-Roels I, Leroux-Roels G. Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Rev Vaccines 2009; 8: 401–23. Johansen K, Nicoll A, Ciancio BC, Kramarz P. Pandemic influenza A(H1N1) 2009 vaccines in the E uropean Union. Euro Surveill 2009; 14: 19361. Kelly H, Barr I. Large trials confirm immunogenicity of H1N1 vaccines. Lancet 2010; 375: 6–9. Doherty PC, Turner SJ, Webby RG, Thomas PG. Influenza and the challenge for immunology. Nat Immunol 2006; 7: 449–55. Swain SL, Agrewala JN, Brown DM, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev 2006; 211: 8–22.
Immunological correlates of protection for the RTS,S candidate malaria vaccine Evidence continues to accumulate that the candidate malaria vaccine RTS,S provides substantial, although not complete, protection against malaria in African children. In The Lancet Infectious Diseases today, Olutu and colleagues1 add to this body of evidence, reporting persistence of protection for at least 15 months after vaccination of Kenyan and Tanzanian infants with the RTS,S candidate malaria vaccine formulated with the AS01 adjuvant. There was no evidence for a reduction in efficacy from that reported during the first 8 months of follow-up of this trial (around 50% efficacy).2 This formulation of RTS,S is being used in a large phase 3 trial (NCT00866619) taking place in 11 centres in Africa, with the first results expected at the end of 2011. Development of the RTS,S candidate malaria vaccine to the point at which a large phase 3 trial could be launched www.thelancet.com/infection Vol 11 February 2011
has taken more than a decade3 and progress has been hampered by the absence of an immunological correlate of protection in vaccinated individuals. Studies done to investigate antigen concentration, dosage schedule, and the best adjuvant have had to use either human challenge studies or studies in endemic areas with clinical malaria as their primary endpoint. Studies in endemic areas have been possible because malaria infection is widespread in children in such places, but these phase 2 trials have, nevertheless, usually needed several hundred children to obtain sufficient statistical power. Development of RTS,S and related vaccines would have been easier had an immunological measurement that reliably predicted protection against malaria infection been available. The RTS,S candidate malaria vaccine is based on the Plasmodium falciparum circumsporozoite protein, which
Published Online January 14, 2011 DOI:10.1016/S14733099(11)70001-9 See Articles page 102
75
Comment
is present in large amounts on the surface of sporozoites and is also expressed by liver schizonts. Thus, immunity conferred by the RTS,S vaccine could act by attacking sporozoites during the short time in which they are in the circulation, disabling them and preventing them from invading liver cells, or by attacking liver schizonts. RTS,S candidate malaria vaccines induce very high titres of anti-circumsporozoite antibodies, much higher titres than are produced by repeated natural infections— these antibodies have, therefore, been assumed to have an important role in the protection against malaria provided by this vaccine. There is quite strong evidence to support this contention. In volunteer challenge studies, recorded antibody titres are generally higher in protected volunteers than they are in volunteers who develop malaria, but there has usually been some overlap between protected and unprotected individuals and no clear threshold has been identified that defines protection.4–6 Field studies have generally shown a similar trend, although with some discordant results. The mean antibody titre was higher in RTS,S/AS02-vaccinated Gambian adults,7 Mozambican infants,8 and Tanzanian infants9 who did not contract malaria than it was in those who did, but there was overlap between groups and no clear threshold. No relation between anticircumsporozoite antibody titres and protection was identified in Mozambican children aged 1–4 years.10 Olutu and colleagues1 report a relation between antibody titres measured on average 4·5 months after the last dose of vaccine but not with titres measured 1 month afterwards, suggesting that antibody kinetics might be involved in conferring protection. Perhaps those with the most rapid drop in titre were most at risk. By use of a two-group model, Olutu and colleagues concluded that a titre in the range of 35–45 EU/mL gave the best discrimination between those who were susceptible and those who were not. Whether this would be the case in other populations needs to be investigated. This could be done in the phase 3 trial being done in multiple centres. RTS,S candidate malaria vaccines induce a strong CD4 T-cell response characterised by the production of inflammatory cytokines such as interferon γ, which could contribute to killing of liver schizonts. As in the case of anti-circumsporozoite antibody, vaccinated volunteers who are protected against malaria have stronger CD4 T-cell responses than do susceptible individuals, but there is overlap between groups and no 76
clear threshold.11,12 Less evidence exists for an association between protection and activated CD8 cytotoxic T cells, although these T cells could play some part in the protection provided by the vaccine.13 Identification of an immunological measurement that provides a reliable measure of clinical protection in RTS-vaccinated individuals from all populations might never be possible. However, the need for such a correlate will become less if the phase 3 trial of the RTS,S/AS01 confirms the promise shown in the study done in Kenya and Tanzania,1 and RTS,S/AS01 becomes the first malaria vaccine to be licensed and widely deployed. Brian Greenwood Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK [email protected] London School of Hygiene and Tropical Medicine was a subcontractor on a grant from the Malaria Vaccine Initiative (MVI), which supported the RTS,S vaccine trial in Tanzania. The author is an investigator on a related grant from MVI for an RTS,S vaccine trial in Ghana. 1
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Olutu A, Lusingu J, Leach A, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis 2011; published online Jan 14. DOI:10.1016/S1473-3099(11)70001-9. Bejon P, Lusingu J, Olutu A, et al. Efficacy of RTS.S/ASO1E against malaria in children 5 to 17 months of age. N Engl J Med 2008; 359: 2521–32. Casares S, Brumeanu T-D, Richie TL. The RTS,S malaria vaccine. Vaccine 2010; 28: 4880–94. Gordon DM, McGovern TW, Krzych U, et al. Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J Infect Dis 1995: 171: 1576–85. Kester KE, McKinney DA, Tornieporth N, et al. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum infections. J Infect Dis 2001; 183: 640–47. Kester KE, Cummings JF, Ockenhouse CF, et al. Phase 2a trial of 0, 1, and 3 month and 0,7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research. Vaccine 2008; 26: 2191–202. Bojang KA, Milligan PJ, Pinder M, et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 2001; 358: 1927–34. Aponte JJ, Aide P,Renom M, et al. Safety of RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique; a double blind randomised controlled phase I/IIb trial. Lancet 2007; 370: 1543–51. Abdulla S, Oberholzer R, Juma O, et al. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008; 359: 2533–44. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02 vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004; 364: 1411–20. Sun P, Schwenk R, White K, et al. Protective immunity with malaria vaccine, RTS,S is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ cells producing IFN-gamma. J Immunol 2003; 171: 6961–67. Kester KE, Cummings JF, Ofori-Anyinam O, et al. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/ AS02A in malaria-naive adults: safety, efficacy and immunologic associates of protection. J Infect Dis 2009; 200: 337–46. Barbosa A, Naniche D, Aponte JJ, et al. Plasmodium falciparum-specific cellular immune responses after immunization with RTS,S/AS02D candidate malaria vaccine in infants living in an area of high endemicity in Mozambique. Infect Immun 2009; 77: 4502–09.
www.thelancet.com/infection Vol 11 February 2011
immune responses induced by the two vaccines compare is unknown. The ultimate question that remains is whether higher antibody responses as recorded in the study by Nicholson and colleagues translate into superior protection. Comparison of vaccine effectiveness data in countries where different H1N1 pandemic vaccines have been used side by side in comparable populations will hopefully shed some light on this important issue.
4
5
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*Geert Leroux-Roels, Isabel Leroux-Roels Centre for Vaccinology, Ghent University and Hospital, Ghent, Belgium [email protected] GL-R has received payment as a consultant, for lectures, and to cover travel and accommodation from GSK Biologicals and has received payment as a consultant from Novartis Vaccines and Diagnostics. IL-R has received payment for a lecture and to cover travel and accommodation from GSK Biologicals and has received payment for a lecture from Sanofi Pasteur. 1
2 3
Nicholson KG, Abrams KR, Batham S, et al. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-tohead trial. Lancet Infect Dis 2010; published online Dec 17. DOI:10.1016/S1473-3099(10)70296-6. Stephenson I, Heath A, Major D, et al. Reproducibility of serologic assays for influenza virus A (H5N1). Emerg Infect Dis 2009; 15: 1252–59. Waddington CS, Walker WT, Oeser C, et al. Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months–12 years: open label, randomised, parallel group, multicentre study. BMJ 2010; 340: c2649.
8
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Waddington C, Andrews N, Hoschler K, et al. Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03B/oil-in-water emulsion-adjuvanted (AS03B) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. Health Technol Assess 2010; 14: 1–130. Leroux-Roels I, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370: 580–89. Rumke HC, Bayas JM, de Juanes JR, et al. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine 2008; 26: 2378–88. Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Devaster JM. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine 2010; 28: 1740–45. Clark TW, Pareek M, Hoschler K, et al. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med 2009; 361: 2424–35. Girard MP, Katz J, Pervikov Y, Palkonyay L, Kieny MP. Report of the 6th meeting on the evaluation of pandemic influenza vaccines in clinical trials World Health Organization, Geneva, Switzerland, 17–18 February 2010. Vaccine 2010; 28: 6811–20. Leroux-Roels I, Leroux-Roels G. Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Rev Vaccines 2009; 8: 401–23. Johansen K, Nicoll A, Ciancio BC, Kramarz P. Pandemic influenza A(H1N1) 2009 vaccines in the E uropean Union. Euro Surveill 2009; 14: 19361. Kelly H, Barr I. Large trials confirm immunogenicity of H1N1 vaccines. Lancet 2010; 375: 6–9. Doherty PC, Turner SJ, Webby RG, Thomas PG. Influenza and the challenge for immunology. Nat Immunol 2006; 7: 449–55. Swain SL, Agrewala JN, Brown DM, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev 2006; 211: 8–22.
Immunological correlates of protection for the RTS,S candidate malaria vaccine Evidence continues to accumulate that the candidate malaria vaccine RTS,S provides substantial, although not complete, protection against malaria in African children. In The Lancet Infectious Diseases today, Olutu and colleagues1 add to this body of evidence, reporting persistence of protection for at least 15 months after vaccination of Kenyan and Tanzanian infants with the RTS,S candidate malaria vaccine formulated with the AS01 adjuvant. There was no evidence for a reduction in efficacy from that reported during the first 8 months of follow-up of this trial (around 50% efficacy).2 This formulation of RTS,S is being used in a large phase 3 trial (NCT00866619) taking place in 11 centres in Africa, with the first results expected at the end of 2011. Development of the RTS,S candidate malaria vaccine to the point at which a large phase 3 trial could be launched www.thelancet.com/infection Vol 11 February 2011
has taken more than a decade3 and progress has been hampered by the absence of an immunological correlate of protection in vaccinated individuals. Studies done to investigate antigen concentration, dosage schedule, and the best adjuvant have had to use either human challenge studies or studies in endemic areas with clinical malaria as their primary endpoint. Studies in endemic areas have been possible because malaria infection is widespread in children in such places, but these phase 2 trials have, nevertheless, usually needed several hundred children to obtain sufficient statistical power. Development of RTS,S and related vaccines would have been easier had an immunological measurement that reliably predicted protection against malaria infection been available. The RTS,S candidate malaria vaccine is based on the Plasmodium falciparum circumsporozoite protein, which
Published Online January 14, 2011 DOI:10.1016/S14733099(11)70001-9 See Articles page 102
75
Comment
is present in large amounts on the surface of sporozoites and is also expressed by liver schizonts. Thus, immunity conferred by the RTS,S vaccine could act by attacking sporozoites during the short time in which they are in the circulation, disabling them and preventing them from invading liver cells, or by attacking liver schizonts. RTS,S candidate malaria vaccines induce very high titres of anti-circumsporozoite antibodies, much higher titres than are produced by repeated natural infections— these antibodies have, therefore, been assumed to have an important role in the protection against malaria provided by this vaccine. There is quite strong evidence to support this contention. In volunteer challenge studies, recorded antibody titres are generally higher in protected volunteers than they are in volunteers who develop malaria, but there has usually been some overlap between protected and unprotected individuals and no clear threshold has been identified that defines protection.4–6 Field studies have generally shown a similar trend, although with some discordant results. The mean antibody titre was higher in RTS,S/AS02-vaccinated Gambian adults,7 Mozambican infants,8 and Tanzanian infants9 who did not contract malaria than it was in those who did, but there was overlap between groups and no clear threshold. No relation between anticircumsporozoite antibody titres and protection was identified in Mozambican children aged 1–4 years.10 Olutu and colleagues1 report a relation between antibody titres measured on average 4·5 months after the last dose of vaccine but not with titres measured 1 month afterwards, suggesting that antibody kinetics might be involved in conferring protection. Perhaps those with the most rapid drop in titre were most at risk. By use of a two-group model, Olutu and colleagues concluded that a titre in the range of 35–45 EU/mL gave the best discrimination between those who were susceptible and those who were not. Whether this would be the case in other populations needs to be investigated. This could be done in the phase 3 trial being done in multiple centres. RTS,S candidate malaria vaccines induce a strong CD4 T-cell response characterised by the production of inflammatory cytokines such as interferon γ, which could contribute to killing of liver schizonts. As in the case of anti-circumsporozoite antibody, vaccinated volunteers who are protected against malaria have stronger CD4 T-cell responses than do susceptible individuals, but there is overlap between groups and no 76
clear threshold.11,12 Less evidence exists for an association between protection and activated CD8 cytotoxic T cells, although these T cells could play some part in the protection provided by the vaccine.13 Identification of an immunological measurement that provides a reliable measure of clinical protection in RTS-vaccinated individuals from all populations might never be possible. However, the need for such a correlate will become less if the phase 3 trial of the RTS,S/AS01 confirms the promise shown in the study done in Kenya and Tanzania,1 and RTS,S/AS01 becomes the first malaria vaccine to be licensed and widely deployed. Brian Greenwood Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK [email protected] London School of Hygiene and Tropical Medicine was a subcontractor on a grant from the Malaria Vaccine Initiative (MVI), which supported the RTS,S vaccine trial in Tanzania. The author is an investigator on a related grant from MVI for an RTS,S vaccine trial in Ghana. 1
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Olutu A, Lusingu J, Leach A, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis 2011; published online Jan 14. DOI:10.1016/S1473-3099(11)70001-9. Bejon P, Lusingu J, Olutu A, et al. Efficacy of RTS.S/ASO1E against malaria in children 5 to 17 months of age. N Engl J Med 2008; 359: 2521–32. Casares S, Brumeanu T-D, Richie TL. The RTS,S malaria vaccine. Vaccine 2010; 28: 4880–94. Gordon DM, McGovern TW, Krzych U, et al. Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J Infect Dis 1995: 171: 1576–85. Kester KE, McKinney DA, Tornieporth N, et al. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum infections. J Infect Dis 2001; 183: 640–47. Kester KE, Cummings JF, Ockenhouse CF, et al. Phase 2a trial of 0, 1, and 3 month and 0,7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research. Vaccine 2008; 26: 2191–202. Bojang KA, Milligan PJ, Pinder M, et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 2001; 358: 1927–34. Aponte JJ, Aide P,Renom M, et al. Safety of RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique; a double blind randomised controlled phase I/IIb trial. Lancet 2007; 370: 1543–51. Abdulla S, Oberholzer R, Juma O, et al. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008; 359: 2533–44. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02 vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004; 364: 1411–20. Sun P, Schwenk R, White K, et al. Protective immunity with malaria vaccine, RTS,S is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ cells producing IFN-gamma. J Immunol 2003; 171: 6961–67. Kester KE, Cummings JF, Ofori-Anyinam O, et al. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/ AS02A in malaria-naive adults: safety, efficacy and immunologic associates of protection. J Infect Dis 2009; 200: 337–46. Barbosa A, Naniche D, Aponte JJ, et al. Plasmodium falciparum-specific cellular immune responses after immunization with RTS,S/AS02D candidate malaria vaccine in infants living in an area of high endemicity in Mozambique. Infect Immun 2009; 77: 4502–09.
www.thelancet.com/infection Vol 11 February 2011