A Cluster-Randomized Effectiveness Trial of Vi Typhoid Vaccine in India

Sur, Dipika; Ochiai, R. Leon; Bhattacharya, Sujit; Ganguly, Nirmal Kumar; Ali, Mohammad; Manna, Byomkesh; Donner, Allan; Kanungo, Suman; Park, Jin Kyung; Puri, Mahesh; Kim, Deok Ryun; Dutta, D; Bhaduri, Barnali; Acosta, Camilo J.; Clemens, John D.

doi:10.1056/nejmoa0807521

Cited by 200 publications

(197 citation statements)

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“…The role of the humoral immune response is not as well defined. Many large-scale field trials have demonstrated that S. Typhi-specific antibodies are produced in a majority of subjects following vaccination or natural illness, but the function or mechanism of protection provided by S. Typhi-specific antibodies is currently uncharacterized (8,14,23,24,31,32,39,46). A better understanding of the function of antibodies mounted in response to disease or vaccination addresses major challenges in understanding humoral immune responses to typhoid disease and aids in the evaluation of new typhoid vaccines.…”

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confidence: 99%

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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Although vaccines have been available for over a century, a correlate of protection for typhoid fever has yet to be identified. Antibodies are produced in response to typhoid infection and vaccination and are generally used as the gold standard for determining vaccine immunogenicity, even though their role in clearance of Salmonella enterica serovar Typhi infections is poorly defined. Here, we describe the first functional characterization of S. Typhi-specific antibodies following vaccination with a new vaccine, M01ZH09 (Ty2 ⌬aroC ⌬ssaV). We determined that postvaccination sera increased the uptake of wild-type S. Typhi by human macrophages up to 2.3-fold relative to prevaccination (day 0) or placebo samples. These results were recapitulated using immunoglobulins purified from postvaccination serum, demonstrating that antibodies were largely responsible for increases in uptake. Imaging verified that macrophages internalized 2-to 9.5-fold more S. Typhi when the bacteria were opsonized with postvaccination sera than when the bacteria were opsonized with day 0 or placebo sera. Once inside macrophages, the survival of S. Typhi was reduced as much as 50% when opsonized with postvaccination sera relative to day 0 or placebo serum samples. Lastly, bactericidal assays indicated that antibodies generated postvaccination were recognized by complement factors and assisted in killing S. Typhi: mean postvaccination bactericidal antibody titers were higher at all time points than placebo and day 0 titers. These data clearly demonstrate that there are at least two mechanisms by which antibodies facilitate killing of S. Typhi. Future work could lead to improved immunogenicity tests associated with vaccine efficacy and the identification of correlates of protection against typhoid fever.

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confidence: 99%

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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“…Inter-individual variability in immune response to peptide vaccines has been documented and a number of polymorphic loci in genes related to both innate and adaptive immune systems have been found to be associated with antibody response to vaccines (Sur et al 2009). However, little is known about genomics of immune response for polysaccharide vaccines.…”

Section: Discussionmentioning

confidence: 99%

“…The extent of variation in immune response has been extensively studied for some vaccines. Primary failure, as assessed by post-vaccination antibody levels, occurs in a significant proportion of vaccinees; for example, 2-10% for measles vaccine (Poland 1998;Poland et al 1999), 5-20% for hepatitis B vaccine (Milich and Leroux-Roels 2003;Zuckerman 1996), and 23-40% for typhoid vaccine (Gupta et al 2008;Sur et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Genetic determinants of immune-response to a polysaccharide vaccine for typhoid

Majumder

Staats

Sarkar-Roy

et al. 2009

HUGO J

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Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response to which is T-cell independent. Little is known about whether genetic variation among vaccinees associates with variation in their antibody response to a polysaccharide vaccine. We conducted a study on 1,000 individuals resident in an area at high-risk for typhoid; vaccinated them with the typhoid vaccine, measured their antibody response to the vaccine, assayed [2,000 curated SNPs chosen from 283 genes that are known to participate in immune-response; and analyzed these data using a strategy to (a) minimize the statistical problems associated with testing of multiple hypotheses, and (b) internally cross-validate inferences, using a half-sample design, with little loss of statistical power. The first stage analysis, using the first half-sample, identified 54 SNPs in 43 genes to be significantly associated with immune response. In the second-stage, these inferences were cross-validated using the second half-sample. First-stage results of only 8 SNPs (out of 54) in 7 genes (out of 43) were cross-validated. We tested additional SNPs in these 7 genes, and found 8 more SNPs to be significantly associated. Haplotypes constructed with these SNPs in these 7 genes also showed significant association. These 7 genes are DEFB1, TLR1, IL1RL1, CTLA4, MAPK8, CD86 and IL17D. The overall picture that has emerged from this study is that (a) immune response to polysaccharide antigens is qualitatively different from that to protein antigens, and (b) polymorphisms in genes involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signaling and eventual production of antimicrobial peptides are associated with antibody response to the polysaccharide vaccine for typhoid.

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“…Corresponding serological assays have been developed and provide correlates of protection to support vaccine licensure. Both injectable and oral typhoid vaccines can provide herd protection when vaccine coverage is adequate [38][39][40]. Because Vi polysaccharide alone, as for other carbohydrate vaccines, is not effective in inducing T-cell-dependent memory responses in young infants, a conjugate vaccine composed of Vi capsular polysaccharide covalently linked to a mutant from Pseudomonas aeruginosa exoprotein A (VirEPA) was developed [41].…”

Section: Typhoid Fever Vaccinesmentioning

confidence: 99%

Vaccines against enteric infections for the developing world

Czerkinsky

Holmgren

2015

Phil. Trans. R. Soc. B

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One contribution of 15 to a discussion meeting issue 'Biological challenges to effective vaccines in the developing world'. Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: -limited knowledge regarding the properties of the gut immune system during early life; -lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines; -lack of correlates/surrogates of mucosal immune protection; and -limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries.There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics.

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A Cluster-Randomized Effectiveness Trial of Vi Typhoid Vaccine in India

Cited by 200 publications

References 21 publications

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Genetic determinants of immune-response to a polysaccharide vaccine for typhoid

Vaccines against enteric infections for the developing world

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