Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review

Christine S Benn, Ane B Fisker, Hilton C Whittle, Peter Aaby, Christine S Benn, Ane B Fisker, Hilton C Whittle, Peter Aaby

Abstract

Background: Live vaccines against measles (MV), tuberculosis (BCG), polio (OPV) and smallpox reduce mortality more than explained by target-disease prevention. The beneficial nonspecific effects (NSEs) of MV are strongest when MV is given in presence of maternal antibodies. We therefore hypothesised that revaccination in presence of prior immunity enhances beneficial NSEs.

Methods: Literature search for studies of revaccination and mortality.

Findings: In two randomised trials (RCTs), two doses versus one dose of MV reduced all-cause mortality by 63% (95% CI: 23-83%) from 9 to 18months of age. In a quasi-experimental study two doses before and after 9months compared with one dose of MV after 9months of age reduced mortality by 59% (25-81%). BCG-revaccination significantly enhanced BCG's effect against overall child mortality in two RCTs. In a natural experiment study of OPV campaigns over a 13-year-period in Guinea-Bissau, each additional dose of OPV was associated with a 13% (4-21%) reduction in mortality rate. The beneficial NSEs of smallpox vaccination for survival increased significantly with the number of smallpox vaccination scars.

Interpretation: Revaccination with live vaccines led to substantial reductions in overall mortality. These findings challenge current understanding of vaccines and may explain the beneficial effects of campaigns with live vaccines.

Keywords: BCG; Boosting; Measles vaccine; Nonspecific effects of vaccines; Oral polio vaccine; Revaccination.

Copyright © 2016 The Ohio State University Wexner Medical Center. Published by Elsevier B.V. All rights reserved.

References

    1. Aaby P., Andersen M., Sodemann M., Jakobsen M., Gomes J., Fernandes M. Reduced childhood mortality after standard measles vaccination at 4–8 months compared with 9–11 months of age. Br. Med. J. 1993;307:1308–1311.
    1. Aaby P., Samb B., Simondon F., Coll Seck A.M., Knudsen K., Whittle H. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. Br. Med. J. 1995;311:481–485.
    1. Aaby P., Bhuyia A., Nahar L., Knudsen K., de Francisco A., Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int. J. Epidemiol. 2003;32:106–115.
    1. Aaby P., Gustafson P., Roth A., Rodrigues A., Fernandes M., Sodemann M., Holmgren B., Stabell Benn C., Garly M.L., Lisse I.M., Jensen H. Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau. Vaccine. 2006;24:5718–5725.
    1. Aaby P., Garly M.L., Nielsen J., Ravn H., Martins C., Balé C., Rodrigues A., Benn C.S., Lisse I.M. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: observations from vaccination trials in Guinea-Bissau. Pediatr. Infect. Dis. J. 2007;26:247–252.
    1. Aaby P., Martins C.L., Garly M.L., Bale C., Andersen A., Rodrigues A., Ravn H., Lisse I.M., Benn C.S., Whittle H. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010;341:c6495.
    1. Aaby P., Roth A., Ravn H., Napirna B.M., Rodrigues A., Lisse I.M., Stensballe L., Diness B.R., Lausch K.R., Lund N., Biering-Sørensen S., Whittle H., Benn C.S. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 2011;204:245–252.
    1. Aaby P., Martins C.L., Garly M.L., Andersen A., Fisker A.B., Claesson M.H., Ravn H., Rodrigues A., Whittle H.C., Benn C.S. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. CID. 2014;59:484–492.
    1. Aaby P., Martins C.L., Ravn H., Rodrigues A., Whittle H.C., Benn C.S. Is early measles vaccination better than later measles vaccination? A review. Trans. R. Soc. Trop. Med. Hyg. 2015;109:16–28.
    1. Aaby P, Ravn H, Benn, CS. The WHO review of the possible non-specific effects of diphtheria-tetanus-pertussis vaccine. Pediatr. Infect. Dis. J. 2016 (epub).
    1. Amouzou A., Habi O., Bensaïd K., Niger Countdown Case Study Working Group Reduction in child mortality in Niger: a countdown to 2015 country case study. Lancet. 2012;380:1169–1178.
    1. Benn C.S., Aaby Diphtheria-tetanus-pertussis vaccination administered after measles vaccine: increased female mortality? Pediatr. Infect. Dis. J. 2012;31:1095–1097.
    1. Benn C.S., Aaby P., Balé C., Michaelsen K.F., Olsen J., George E., Whittle H. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, West Africa. Lancet. 1997;350:101–105.
    1. Benn C.S., Netea M.G., Selin L.K., Aaby P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34:431–439.
    1. Benn C.S., Martins C., Fisker A.B., Garly M.L., Balde I., Rodrigues A., Whittle H., Aaby P. Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau. Vaccine. 2014;32:5468–5474.
    1. Benn C.S., Aaby P., Arts R.J.W., Jensen K.J., Netea M.G., Fisker A.B. An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality. Int. J. Epidemiol. 2015;44:906–918.
    1. Biering-Sørensen S., Aaby P., Napirna B.M., Roth A., Ravn H., Rodrigues A., Whittle H., Benn C.S. Small randomised trial among low-birth-weight children of Bacillus Calmette-Guérin vaccination at first health center contact. Pediatr. Infect. Dis. J. 2012;31:306–308.
    1. Biot C., Rentsch C.A., Gsponer J.R., Birkhäuser F.D., Jusforgues-Saklani H., Lemaître F., Auriau C., Bachmann A., Bousso P., Demangel C., Peduto L., Thalmann G.N., Albert M.L. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl. Med. 2012;4(137):137ra72.
    1. De Valière S., Abate G., Blazevic A., Heuwetz R.M., Hoft D.F. Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies. Infect. Immun. 2005;73:6711.
    1. Fisker A.B., Rodrigues A., Martins C., Byberg S., Thysen S., Pedersen M., Fernandes M., Ravn H., Benn C.S., Aaby P. Reduced mortality after general measles vaccination campaign in rural Guinea-Bissau. Pediatr. Infect. Dis. J. 2015;34:1369–1376.
    1. Higgins J.P.T., Soares-Weiser K., Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. 2014. ( - accessed June 1, 2014)
    1. Holt E.A., Boulos R., Halsey N.A., Boulos L.M., Boulos C. Childhood survival in Haiti: protective effect of measles vaccination. Pediatrics. 1990;86:188–194.
    1. Jensen M.L., Dave S., van der Loeff M.S., da Costa C., Vincent T., Leligdowicz A., Benn C.S., Roth A., Jensen H., Lisse I.M., Whittle H., Aaby P. Vaccinia scars associated with improved survival among adults in rural Guinea-Bissau. PLoS One. 2006;1
    1. Kleinnijenhuis J., Quintin J., Preijers F. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. U. S. A. 2012;109(43):17537–17542.
    1. Kleinnijenhuis J., Quintin J., Preijers F., Benn C.S., Joosten L.A., Jacobs C., van Loenhout J., Xavier R.J., Aaby P., van der Meer J.W., van Crevel R., Netea M.G. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 2014;6:152–158.
    1. Kristensen I., Aaby P., Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000;321:1435–1438.
    1. Kuhn T. The University of Chicago Press; Chicago: 1962. The Structure of Scientific Revolutions.
    1. Lund N., Andersen A., Hansen A.S., Jepsen F.S., Barbosa A.G., Biering-Sørensen S., Ravn H., Aaby P., Benn C.S. The effect of oral polio vaccine at birth on mortality. A randomized trial. CID. 2015 61, 1504-1511.
    1. Martins C.L., Benn C.S., Andersen A., Balé C., Schaltz-Buchholzer F., Do V.A., Rodrigues A., Aaby P., Ravn H., Whittle H., Garly M.L. A randomized trial of a standard dose of Èdmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J. Infect. Dis. 2014;209:1731–1738.
    1. Reickmann A., Villumsen M., Sørup S., Haugaard L.K., Ravn H., Roth A., Baker J.L., Benn C.S., Aaby P. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int. J. Epidemiol. 2016 (epub)
    1. Roth A., Benn C.B., Ravn H., Rodrigues A., Lisse I.M., Yazdanbakhsh M., Whittle H., Aaby P. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ. 2010;340:c671.
    1. Selin L.K., Brehm M.A., Naumov Y.N., Cornberg M., Kim S.K., Clute S.C., Welsh R.M. Memory of mice and men: CD8 + T-cell cross-reactivity and heterologous immunity. Immunol. Rev. 2006;211:164–181.
    1. Sergent E., Catanei A., Ducros-Rougebief H. Prèmunition antituberculeuse par le BCG. Campagne porsuivie depuis 1935 sur 21.244 nouveau-nés vaccines et 20.063 non vaccines. Arch L'Institut Pasteur D'Algerie. 1954;32:1–8.
    1. Silva M., Lasunskaia E., Silva W. Repeated inoculations of Mycobacterium bovis Bacille Calmette-Guérin (BCG) are needed to induce a strong humoral immune response against antigens expressed by the bacteria. Open J. Immunol. 2013;3:71–81.
    1. Sørup S., Benn C.S., Poulsen A., Krause T., Aaby P., Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA. 2014;311:826–835.
    1. Sørup S., Stensballe L.G., Krause T.G., Aaby P., Benn C.S., Ravn H. Oral polio vaccination and hospital admissions with non-polio infections in Denmark: nationwide retrospective cohort study. Open Forum Infect. Dis. 2015;3(1):ofv204.
    1. Storgaard L., Rodrigues A., Nielsen B.U., Ravn H., Benn C.B., Aaby P., Fisker A.B. Does a BCG scar protect against childhood hospitalization and death in rural Guinea-Bissau? CID. 2015;61:950–959.
    1. Strategic Advisory Group of Experts on Immunization Wkly Epidemiol. Rec. 2014;89:233–235.
    1. Veirum J.E., Sodemann M., Biai S., Jakobsen M., Garly M.L., Hedegaard K., Jensen H., Aaby P. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2005;23:1197–1203.

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