Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Clinical and Vaccine Immunology : CVI logoLink to Clinical and Vaccine Immunology : CVI
. 2013 Oct;20(10):1487–1490. doi: 10.1128/CVI.00465-13

Comparing the Roles of Antibodies to Nontyphoidal Salmonella enterica in High- and Low-Income Countries and Implications for Vaccine Development

Calman A MacLennan a,b,, Sharon M Tennant c,d
PMCID: PMC3807204  PMID: 23904457

TEXT

The article by Trebicka et al. (1) in the current issue of Clinical and Vaccine Immunology, on antibodies to Salmonella among adults and children in the United States, is paradoxically important for our understanding of immunity to nontyphoidal Salmonella (NTS) globally and the development of a much-needed vaccine for Africa. In recent years, there has been a growing awareness of the major public health problem attributable to NTS infections in sub-Saharan Africa (25). Unlike the self-limiting gastroenteritis commonly seen in high-income countries (6), the presentation in Africa is often with life-threatening invasive NTS (iNTS) disease (2, 3, 5). This usually manifests as bacteremia, where fever may be the only symptom, but also as meningitis (7).

Incidence levels of iNTS are around 500 cases/100,000 people/year among African children under 2 years (8, 9), with case fatality rates of 20 to 25% (2). Diagnosing iNTS without blood culture facilities is particularly difficult, and there is an increasing frequency of antibiotic resistance, with no vaccine available for use in humans (3). An effective vaccine could have an enormous beneficial impact on health care in the continent. This would make a strong positive contribution to achieving the Millennium Development Goals, particularly goal 4, the reduction of child mortality (10). As with young children, HIV-infected individuals of all ages are highly susceptible to iNTS disease (11, 12), and there are well-recognized clinical associations with malaria (13), anemia (14), and malnutrition (15).

The high prevalence of iNTS disease in Africa and its relative rarity in high-income countries may relate to the specific microbiological features of the circulating strains and the transmission of the bacteria in Africa (3). Recently, NTS isolates in Africa have been shown to be genetically different from those present elsewhere. Salmonella enterica serovar Typhimurium, the most common serovar responsible for iNTS disease in Africa, with a distinct multilocus sequence type, ST313, has been implicated in the appearance of epidemic iNTS disease (4, 16). This pathovar is rarely found outside Africa and has genomic features in common with S. enterica serovar Typhi, most notably the presence of high levels of genome degradation (16). However, relatively little is known about its phenotypic features that are associated with invasive disease. Transmission of iNTS in Africa also appears to be different from the food-borne or animal-related transmission commonly associated with Salmonella infections in high-income countries. There is evidence for human-to-human spread as the main form of transmission in Africa (17, 18). This may be facilitated by the lower levels of sanitation and the lack of availability of clean water in much of the continent.

Apart from the distinct bacterial genotype associated with iNTS, differences in immunological status are likely to have an impact on the occurrence of iNTS disease (3). This is not least because early childhood can represent an immunologically naive state and the clinical associations with iNTS disease in Africa (HIV, malnutrition, malaria, and anemia) can all have an impact on immunity. A proper understanding of immunity to NTS is required for the development of a vaccine against iNTS disease for Africa. Hence, studies of immunity to NTS are important and should be conducted in high-income countries as well as low-income countries. Mechanistic immunological research into Salmonella infections in high-income countries has tended to focus on disease in mice, resulting in an unusual paradigm in which the more-recent studies on immunity to iNTS in humans have been conducted in low-income countries (19, 20). The current study by Trebicka et al. represents a welcome step toward redressing this imbalance and attaining a more holistic overview of immunity to NTS infections at a global level.

It is key for us to acquire a fuller understanding of the mechanisms of protective immunity and to identify the relevant target antigens for developing such immunity (21). Cell-mediated immunity has long been viewed as essential for protection against this facultative intracellular pathogen (22). While cell-mediated immunity is important for clearing intracellular disease, it is ineffective at preventing fatal bacteremia. In contrast, bacteremia can be countered by antibody acting both directly through complement-mediated killing (19) and indirectly through opsonic mechanisms and blood cell phagocytes (20). There is strong epidemiological evidence from Africa for the protective effect of antibody, with markedly reduced numbers of cases of iNTS disease being associated with placentally transferred IgG and the acquisition of antibody to NTS with age (19).

Relatively little work on the key targets of protective, acquired immunity to iNTS in Africa has been published. Investigation into the underlying mechanisms responsible for the link between HIV infection and fatal iNTS disease in African adults found that sera from some HIV-infected individuals were unable to kill S. Typhimurium in vitro (23). That study went on to show that the lack of killing was associated with the presence of high levels of antibodies targeting the O antigen of S. Typhimurium LPS. When purified, such antibodies blocked in vitro complement-mediated killing of Salmonella by antibodies from healthy individuals.

Interestingly, Trebicka and colleagues have shown bactericidal activity against S. Typhimurium in deidentified sera from healthy adults and children (6 months to 5 years of age) (n = 49) attending clinics in Boston, as has been found in Africans (19, 23). Comparison with the results of work from Malawi has been facilitated by the use of similar methodologies in the different studies. The main obvious difference between these studies was the use of a common laboratory strain of S. Typhimurium (SL1344; ST19, a genotype common worldwide) by Trebicka et al. and the use of the invasive S. Typhimurium ST313 isolate, D23580, by the African studies (16, 19, 20, 23). As shown for African children (19), the need for both antibody and complement for cell-free bactericidal activity was confirmed. Although all sera from children in the Boston study were able to kill SL1344, the level of killing was significantly lower than that effected by sera from adults, presumably due to lower levels of antibodies to S. Typhimurium.

Trebicka et al. detected IgM and IgG antibodies against S. Typhimurium LPS in their sera and speculated that the bactericidal antibodies are specific for LPS. Removal of bactericidal activity after preabsorption with LPS from S. Typhimurium, but not LPS from E. coli, supports this concept. It suggests that the specificity of these bactericidal antibodies is for the O antigen of LPS, since this is the most variable moiety of LPS among different species and serovars of Gram-negative bacteria. The findings may appear contradictory to those from studies in Malawi that focused on HIV-infected adults (23). However, these HIV-infected individuals had marked immune dysregulation. Many of them had CD4 counts less than 200 cells/μl, and none was on antiretroviral therapy. All had hypergammaglobulinemia. Lack of bactericidal activity and inhibition of the bactericidal activity of control serum was observed in a subset of HIV-infected sera containing the highest concentrations of total and anti-LPS IgG antibodies. The inhibitory effect could be recapitulated using affinity-purified anti-LPS IgG from either HIV-infected or non-HIV-infected bactericidal sera provided they were concentrated to the same high levels present in the HIV-infected inhibitory sera (23).

Further work on the African sera has demonstrated that at concentrations found in non-HIV-infected sera and most HIV-infected sera, these anti-LPS antibodies are bactericidal (24). In addition, absorption studies similar to the ones conducted by Trebicka et al. show that bactericidal activity can be curtailed in the African sera by removal of anti-LPS antibodies (25). Trebicka et al. speculated that the contrast between bactericidal and inhibitory anti-LPS antibodies from Africa and the United States might result from exposure to the ST313 pathovar of S. Typhimurium.

Against this, a recent study into the immunogenicity of the S. Typhimurium ST313 D23580 isolate demonstrates that bactericidal antibodies are induced in mice immunized with this strain (26) and that glycoconjugates consisting of D23580 O antigen linked to cross-reacting material 197 (CRM197) induce bactericidal antibodies against D23580 (27). Passive transfer to naive mice of immune sera from mice immunized with an S. enterica serovar Enteritidis O-antigen flagellin glycoconjugate vaccine has been shown to be protective against an invasive S. Enteritidis isolate from Mali, West Africa (28). Furthermore, mice immunized with a live attenuated vaccine strain derived from another African ST313 isolate also developed bactericidal antibodies against strains of this genotype (29).

Overall, the results of this mechanistic study by Trebicka et al., conducted in a high-income country, have remarkable concordance with those of African studies. Although, at very high concentrations, anti-Salmonella LPS IgG antibodies can exert an inhibitory effect on in vitro complement-mediated killing of S. Typhimurium (23), at most concentrations they are bactericidal (24). Perhaps the most surprising finding of the Boston study is the almost-universal presence of anti-Salmonella LPS antibodies in a collection of sera from healthy children and adults from that city. The authors speculate two possible reasons for this: first, the development of cross-reactive antibodies against S. Typhimurium LPS from exposure to environmental LPSs from other organisms, and second, the occurrence of subclinical infections with S. Typhimurium leading to the development of these antibodies. Both explanations are plausible. While the former will require more than exposure to E. coli LPS, the latter is not as strange as it may appear. Asymptomatic infections with Salmonella, when looked for, are more common than expected (30). Moreover, when HIV/AIDS first emerged in high-income countries, severe disease with NTS was a common presentation (31, 32), suggesting that exposure to these bacteria is more widespread than appreciated.

One of the 49 sera examined in the Boston study was unable to kill S. Typhimurium and was able to inhibit the killing of these bacteria by control sera. The likely mechanism appears to be different from that in HIV-infected African adults. Using absorption studies, the authors were able to implicate anti-Salmonella LPS IgM, rather than IgG. Surprisingly, this was associated with a decreased level of complement deposition, rather than the high levels of complement deposition seen in the African studies. IgM is normally a potent activator of complement on Salmonella (33), and the authors speculate that structural idiosyncrasies of these particular IgM molecules might interfere with complement binding. It will be interesting to see whether such a mechanism can be demonstrated in a future study. The observation suggests that there are different mechanisms by which antibody-mediated killing of Salmonella can be blocked.

In conclusion, the findings of the Boston study, together with ongoing emerging work from Africa, indicate an important role for anti-LPS antibodies for complement-mediated killing of Salmonella and that the induction of such antibodies may be an effective vaccine strategy. The bactericidal and protective efficacies of antibodies to Salmonella outer membrane proteins (23, 34, 35) and flagellin (36) have also been described. The presence of such protein antigens in a vaccine may be advantageous, since they have the added potential benefit of being able to activate Salmonella-specific CD4+ T helper cells. Together, these results suggest that glycoconjugate vaccines in which Salmonella LPS O antigen is coupled to a Salmonella-specific or other protein can elicit protective antibodies and would be effective in reducing iNTS disease in Africa.

Footnotes

Published ahead of print 31 July 2013

The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.

REFERENCES

  • 1.Trebicka E, Jacob S, Pirzai W, Hurley BP, Cherayil BJ. 2013. Role of antilipopolysaccharide antibodies in serum bactericidal activity against Salmonella enterica serovar Typhimurium in healthy adults and children in the United States. Clin. Vaccine Immunol. 20:1491–1498 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA. 2012. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 379:2489–2499 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.MacLennan CA, Levine MM. 2013. Invasive nontyphoidal Salmonella disease in Africa: current status. Expert Rev. Anti Infect. Ther. 11:443–446 [DOI] [PubMed] [Google Scholar]
  • 4.Okoro CK, Kingsley RA, Connor TR, Harris SR, Parry CM, Al-Mashhadani MN, Kariuki S, Msefula CL, Gordon MA, de Pinna E, Wain J, Heyderman RS, Obaro S, Alonso PL, Mandomando I, MacLennan CA, Tapia MD, Levine MM, Tennant SM, Parkhill J, Dougan G. 2012. Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa. Nat. Genet. 44:1215–1221 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Reddy EA, Shaw AV, Crump JA. 2010. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect. Dis. 10:417–432 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hohmann EL. 2001. Nontyphoidal salmonellosis. Clin. Infect. Dis. 32:263–269 [DOI] [PubMed] [Google Scholar]
  • 7.Molyneux EM, Mankhambo LA, Phiri A, Graham SM, Forsyth H, Phiri A, Walsh AL, Wilson LK, Molyneux ME. 2009. The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997–2006. Ann. Trop. Paediatr. 29:13–22 [DOI] [PubMed] [Google Scholar]
  • 8.Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, Methogo BG, Doucka Y, Flamen A, Mordmuller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Nhamuave A, Quelhas D, Bassat Q, Mandjate S, Macete E, Alonso P, Abdulla S, Salim N, Juma O, Shomari M, Shubis K, Machera F, Hamad AS, Minja R, Mtoro A, Sykes A, Ahmed S, Urassa AM, Ali AM, Mwangoka G, Tanner M, Tinto H, D'Alessandro U, Sorgho H, Valea I, Tahita MC, Kabore W, Ouedraogo S, Sandrine Y, Guiguemde RT, Ouedraogo JB, Hamel MJ, Kariuki S, Odero C, Oneko M, Otieno K, Awino N, Omoto J, Williamson J, Muturi-Kioi V, Laserson KF, Slutsker L, Otieno W, Otieno L, Nekoye O, Gondi S, Otieno A, Ogutu B, Wasuna R, Owira V, Jones D, Onyango AA, Njuguna P, Chilengi R, Akoo P, Kerubo C, Gitaka J, Maingi C, Lang T, Olotu A, Tsofa B, Bejon P, Peshu N, Marsh K, Owusu-Agyei S, Asante KP, Osei-Kwakye K, Boahen O, Ayamba S, Kayan K, Owusu-Ofori R, Dosoo D, Asante I, Adjei G, Adjei G, Chandramohan D, Greenwood B, Lusingu J, Gesase S, Malabeja A, Abdul O, Kilavo H, Mahende C, Liheluka E, Lemnge M, Theander T, Drakeley C, Ansong D, Agbenyega T, Adjei S, Boateng HO, Rettig T, Bawa J, Sylverken J, Sambian D, Agyekum A, Owusu L, Martinson F, Hoffman I, Mvalo T, Kamthunzi P, Nkomo R, Msika A, Jumbe A, Chome N, Nyakuipa D, Chintedza J, Ballou WR, Bruls M, Cohen J, Guerra Y, Jongert E, Lapierre D, Leach A, Lievens M, Ofori-Anyinam O, Vekemans J, Carter T, Leboulleux D, Loucq C, Radford A, Savarese B, Schellenberg D, Sillman M, Vansadia P. 2011. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N. Engl. J. Med. 365:1863–1875 [DOI] [PubMed] [Google Scholar]
  • 9.Sigauque B, Roca A, Mandomando I, Morais L, Quinto L, Sacarlal J, Macete E, Nhamposa T, Machevo S, Aide P, Bassat Q, Bardaji A, Nhalungo D, Soriano-Gabarro M, Flannery B, Menendez C, Levine MM, Alonso PL. 2009. Community-acquired bacteremia among children admitted to a rural hospital in Mozambique. Pediatr. Infect. Dis. J. 28:108–113 [DOI] [PubMed] [Google Scholar]
  • 10.United Nations Development Programme The millennium development goals. United Nations Development Program, New York, NY: http://www.undp.org/content/undp/en/home/mdgoverview/ [Google Scholar]
  • 11.Gilks CF, Brindle RJ, Otieno LS, Simani PM, Newnham RS, Bhatt SM, Lule GN, Okelo GB, Watkins WM, Waiyaki PG. 1990. Life-threatening bacteraemia in HIV-1 seropositive adults admitted to hospital in Nairobi, Kenya. Lancet 336:545–549 [DOI] [PubMed] [Google Scholar]
  • 12.Gordon MA, Banda HT, Gondwe M, Gordon SB, Boeree MJ, Walsh AL, Corkill JE, Hart CA, Gilks CF, Molyneux ME. 2002. Non-typhoidal salmonella bacteraemia among HIV-infected Malawian adults: high mortality and frequent recrudescence. AIDS (Lond.) 16:1633–1641 [DOI] [PubMed] [Google Scholar]
  • 13.Mabey DC, Brown A, Greenwood BM. 1987. Plasmodium falciparum malaria and Salmonella infections in Gambian children. J. Infect. Dis. 155:1319–1321 [DOI] [PubMed] [Google Scholar]
  • 14.Calis JC, Phiri KS, Faragher EB, Brabin BJ, Bates I, Cuevas LE, de Haan RJ, Phiri AI, Malange P, Khoka M, Hulshof PJ, van Lieshout L, Beld MG, Teo YY, Rockett KA, Richardson A, Kwiatkowski DP, Molyneux ME, van Hensbroek MB. 2008. Severe anemia in Malawian children. N. Engl. J. Med. 358:888–899 [DOI] [PubMed] [Google Scholar]
  • 15.Bachou H, Tylleskar T, Kaddu-Mulindwa DH, Tumwine JK. 2006. Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda. BMC Infect. Dis. 6:160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Kingsley RA, Msefula CL, Thomson NR, Kariuki S, Holt KE, Gordon MA, Harris D, Clarke L, Whitehead S, Sangal V, Marsh K, Achtman M, Molyneux ME, Cormican M, Parkhill J, MacLennan CA, Heyderman RS, Dougan G. 2009. Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Res. 19:2279–2287 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kariuki S, Revathi G, Gakuya F, Yamo V, Muyodi J, Hart CA. 2002. Lack of clonal relationship between non-typhi Salmonella strain types from humans and those isolated from animals living in close contact. FEMS Immunol. Med. Microbiol. 33:165–171 [DOI] [PubMed] [Google Scholar]
  • 18.Kariuki S, Revathi G, Kariuki N, Kiiru J, Mwituria J, Muyodi J, Githinji JW, Kagendo D, Munyalo A, Hart CA. 2006. Invasive multidrug-resistant non-typhoidal Salmonella infections in Africa: zoonotic or anthroponotic transmission? J. Med. Microbiol. 55:585–591 [DOI] [PubMed] [Google Scholar]
  • 19.MacLennan CA, Gondwe EN, Msefula CL, Kingsley RA, Thomson NR, White SA, Goodall M, Pickard DJ, Graham SM, Dougan G, Hart CA, Molyneux ME, Drayson MT. 2008. The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children. J. Clin. Invest. 118:1553–1562 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Gondwe EN, Molyneux ME, Goodall M, Graham SM, Mastroeni P, Drayson MT, MacLennan CA. 2010. Importance of antibody and complement for oxidative burst and killing of invasive nontyphoidal Salmonella by blood cells in Africans. Proc. Natl. Acad. Sci. U. S. A. 107:3070–3075 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.MacLennan CA. 2013. Antibodies and protection to Salmonella, speaker abstr, p 19 8th Int. Conf. Typhoid Fever Other Invasive Salmonelloses, Dhaka, Bangladesh [Google Scholar]
  • 22.Fields PI, Swanson RV, Haidaris CG, Heffron F. 1986. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc. Natl. Acad. Sci. U. S. A. 83:5189–5193 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.MacLennan CA, Gilchrist JJ, Gordon MA, Cunningham AF, Cobbold M, Goodall M, Kingsley RA, van Oosterhout JJ, Msefula CL, Mandala WL, Leyton DL, Marshall JL, Gondwe EN, Bobat S, Lopez-Macias C, Doffinger R, Henderson IR, Zijlstra EE, Dougan G, Drayson MT, MacLennan IC, Molyneux ME. 2010. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science 328:508–512 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Goh YS, Necchi F, Rondini S, O'Shaughnessy CM, Micoli F, Gavini M, Msefula CL, Gondwe EN, Mandala WL, Gordon MA, Saul A, MacLennan CA. 2013. Bactericidal potential of S. Typhimurium LPS-specific antibodies from HIV-infected African adults, abstr 74, p 12 8th Int. Conf. Typhoid Fever Other Invasive Salmonelloses, Dhaka, Bangladesh [Google Scholar]
  • 25.Siggins MK, Cunningham AF, Silva SS, Necchi F, Coward C, Henderson IR, MacLennan CA. 2013. O-antigen of invasive African nontyphoidal Salmonella is a major target of bactericidal antibodies, abstr 84, p 21 8th Int. Conf. Typhoid Fever Other Invasive Salmonelloses, Dhaka, Bangladesh [Google Scholar]
  • 26.Rondini S, Lanzilao L, Necchi F, O'Shaughnessy CM, Micoli F, Saul A, MacLennan CA. 2013. Invasive African Salmonella Typhimurium induces bactericidal antibodies against O-antigens. Microb. Pathog. 63C:19–23 [DOI] [PubMed] [Google Scholar]
  • 27.Rondini S, Micoli F, Lanzilao L, Stefanetti G, Gavini M, Saul A, MacLennan CA. 2013. Immune response-driven design of glycoconjugate vaccines against NTS, aabstr 99, p 33 8th Int. Conf. Typhoid Fever Other Invasive Salmonelloses, Dhaka, Bangladesh [Google Scholar]
  • 28.Simon R, Wang JY, Boyd MA, Tulapurkar ME, Ramachandran G, Tennant SM, Pasetti M, Galen JE, Levine MM. 2013. Sustained protection in mice immunized with fractional doses of Salmonella enteritidis core and O polysaccharide-flagellin glycoconjugates. PLoS One 8:e64680. 10.1371/journal.pone.0064680 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Boyd MA, Tennant SM, Saague V, Simon R, Muhsen K, Ramachandran G, Pasetti MF, Galen JE, Levine MM. 2013. The development of serum bactericidal assays to evaluate Salmonella vaccines, abstr P13, p 114 16th Annu. Conf. Vaccine Res., Baltimore, MD [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Jertborn M, Haglind P, Iwarson S, Svennerholm AM. 1990. Estimation of symptomatic and asymptomatic Salmonella infections. Scand. J. Infect. Dis. 22:451–455 [DOI] [PubMed] [Google Scholar]
  • 31.Clumeck N, Mascart-Lemone F, de Maubeuge J, Brenez D, Marcelis L. 1983. Acquired immune deficiency syndrome in Black Africans. Lancet i:642. [DOI] [PubMed] [Google Scholar]
  • 32.Jacobs JL, Gold JW, Murray HW, Roberts RB, Armstrong D. 1985. Salmonella infections in patients with the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:186–188 [DOI] [PubMed] [Google Scholar]
  • 33.Robbins JB, Kenny K, Suter E. 1965. The isolation and biological activities of rabbit γM- and γG-anti-Salmonella typhimurium antibodies. J. Exp. Med. 122:385–402 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Gil-Cruz C, Bobat S, Marshall JL, Kingsley RA, Ross EA, Henderson IR, Leyton DL, Coughlan RE, Khan M, Jensen KT, Buckley CD, Dougan G, MacLennan IC, Lopez-Macias C, Cunningham AF. 2009. The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. Proc. Natl. Acad. Sci. U. S. A. 106:9803–9808 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Cunningham AF, Gaspal F, Serre K, Mohr E, Henderson IR, Scott-Tucker A, Kenny SM, Khan M, Toellner KM, Lane PJ, MacLennan IC. 2007. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. 178:6200–6207 [DOI] [PubMed] [Google Scholar]
  • 36.Simon R, Tennant SM, Wang JY, Schmidlein PJ, Lees A, Ernst RK, Pasetti MF, Galen JE, Levine MM. 2011. Salmonella enterica serovar enteritidis core O polysaccharide conjugated to H:g,m flagellin as a candidate vaccine for protection against invasive infection with S. enteritidis. Infect. Immun. 79:4240–4249 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical and Vaccine Immunology : CVI are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES