Different profiles of the human immune response to primary and secondary immunization with an oral Salmonella typhi Ty21a vaccine

doi:10.1016/0264-410X(91)90129-T

Vaccine

Volume 9, Issue 6, June 1991, Pages 423-427

https://doi.org/10.1016/0264-410X(91)90129-T Get rights and content

Abstract

Human immune response to a secondary immunization by the oral route was studied by enumerating specific antibody-secreting cells (ASC) in the peripheral blood, believed to reflect the local immune response in the mucosa. The volunteers had been immunized 1–2 years earlier with live Salmonella typhi Ty21a given orally as three doses of vaccine in enteric-coated capsules (3 x E); their ASC and serum antibody responses have been published. In the present study 17 of the same volunteers received one booster dose of the same vaccine (B-E). Specific ASC appeared in the blood of all volunteers after vaccination, peaked on day 5 and faded away thereafter so that on day 9 specific ASC were detected in only seven subjects. The ASC responses to the single booster dose were significantly higher than those to one dose in primary immunization and at least as high as those of the same volunteers to three doses in primary immunization. Serum antibody responses were not seen in any of the vaccinees after secondary immunization, whereas after primary immunization 60% of these subjects responded. This study shows the presence of immunologic memory also in respect of the human ASC response, and confirms the separate nature of ASC and serum responses.

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Cited by (47)

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The latest omicron variants are emerging with mutations in the receptor binding domain (RBD) that confer immune evasion and resistance against current vaccines. Such variants have raised the peril of future vaccine effectiveness, as leading vaccines target the spike protein. Type-IV hypersensitivity, and other ailments due to the dominant Th1 response by leading vaccines, is also to be resolved. Therefore, vaccine that target diverse SARS-CoV-2 proteins and provide broad-spectrum protection and a balanced Th1 and Th2 response is an indispensable armament against the pandemic. In that prospect, a novel dual expression plasmid pJHL270 was developed and demonstrated the expression of omicron antigens exogenously from Salmonella and endogenously in the host cells. The simultaneous activation of MHC class I and II molecules culminated in a balanced Th1 and Th2 response, which was evident through the upsurge of IgG, IgA antibodies, IgG2a/IgG1 ratio, cytokine responses and CD4+, CD8+ T-lymphocytes. The level of CD44+ cells showed the trigger for Th1 and Th2 balance and memory-cell activation for long-lasting immunity. The level of IFN-γ + cells and neutralizing antibodies signifies the anti-viral response. The vaccine protected the hamsters from BA.5 and BA.2.75 omicron viral-challenge, exhibited a significant reduction in lung viral-load and histopathological lesions. In addition to two-way antigen expression and bilateral immune elicitation, this Salmonella-based vaccine delivery system can be prospectively applied to humans and a broad range of animals as a convenient alternative to viral and chemical vaccine delivery approaches.
Bacteria-enabled oral delivery of a replicon-based mRNA vaccine candidate protects against ancestral and delta variant SARS-CoV-2
2022, Molecular Therapy
Citation Excerpt :
Of note, Salmonella Typhimurium serves as a preclinical organism to study Salmonella Typhi in small laboratory rodents.26 Because a plethora of studies have supported the use of S. Typhi as a vaccine vector in human volunteers,27–29 and live-attenuated S. Typhi is available as a licensed vaccine,30 the use of S. Typhi for further vaccine development provides the possibility of direct translation to humans. The findings have implications for the development of bacteria-enabled replicon-based oral mRNA vaccines against infectious diseases not limited to SARS-CoV-2.
The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolution has resulted in many variants, contributing to the striking drop in vaccine efficacy and necessitating the development of next-generation vaccines to tackle antigenic diversity. Herein we developed a multivalent Semliki Forest virus replicon-based mRNA vaccine targeting the receptor binding domain (RBD), heptad repeat domain (HR), membrane protein (M), and epitopes of non-structural protein 13 (nsp13) of SARS-CoV-2. The bacteria-mediated gene delivery offers the rapid production of large quantities of vaccine at a highly economical scale and notably allows needle-free mass vaccination. Favorable T-helper (Th) 1-dominated potent antibody and cellular immune responses were detected in the immunized mice. Further, immunization induced strong cross-protective neutralizing antibodies (NAbs) against the B.1.617.2 delta variant (clade G). We recorded a difference in induction of immunoglobulin (Ig) A response by the immunization route, with the oral route eliciting a strong mucosal secretory IgA (sIgA) response, which possibly has contributed to the enhanced protection conferred by oral immunization. Hamsters immunized orally were completely protected against viral replication in the lungs and the nasal cavity. Importantly, the vaccine protected the hamsters against SARS-CoV-2-induced pneumonia. The study provides proof-of-principle findings for the development of a feasible and efficacious oral mRNA vaccine against SARS-CoV-2 and its variants.
Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity
2018, Journal of Immunological Methods
Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).
Correlates of protection for enteric vaccines
2017, Vaccine
An immunological Correlate of Protection (CoP) is an immune response that is statistically interrelated with protection. Identification of CoPs for enteric vaccines would help design studies to improve vaccine performance of licensed vaccines in low income settings, and would facilitate the testing of future vaccines in development that might be more affordable. CoPs are lacking today for most existing and investigational enteric vaccines. In order to share the latest information on CoPs for enteric vaccines and to discuss novel approaches to correlate mucosal immune responses in humans with protection, the Foundation Mérieux organized an international conference of experts where potential CoPs for vaccines were examined using case-studies for both bacterial and viral enteric pathogens.
Experts on the panel concluded that to date, all established enteric vaccine CoPs, such as those for hepatitis A, Vi typhoid and poliovirus vaccines, are based on serological immune responses even though these may poorly reflect the relevant gut immune responses or predict protective efficacy. Known CoPs for cholera, norovirus and rotavirus could be considered as acceptable for comparisons of similarly composed vaccines while more work is still needed to establish CoPs for the remaining enteric pathogens and their candidate vaccines.
Novel approaches to correlate human mucosal immune responses with protection include the investigation of gut-originating antibody-secreting cells (ASCs), B memory cells and follicular helper T cells from samples of peripheral blood during their recirculation.
Typhoid Fever Vaccines
2017, Plotkin's Vaccines
Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine
2016, Vaccine
Citation Excerpt :
Since CTB is highly homologous to the LCTBA molecule in MEV [18], it is likely that mucosal memory responses to LTB, and potentially also to CFs and LPS, may be even more long-lived than shown in the present study. ASC responses in blood induced by the oral typhoid vaccine Ty21a also peak slightly earlier after booster compared to primary vaccine doses, administered 1–2 years previously, indicating persistent mucosal memory [19]. These results support that analysis of blood ASC/ALS responses may be a simple approach to assess intestine-derived memory responses after oral immunization in humans and that the method can be applied to different types of vaccines and antigens.
We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia coli (ETEC) vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. coli strains over-expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTBA. Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers (n = 16–19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13–23 months earlier had received two biweekly doses of MEV (II) or MEV + double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory.
Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13–23 months after priming vaccination.
We conclude that MEV induces functional mucosal immunological memory which remains at least 1–2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans.
Clinical trials registration: ISRCTN27096290.

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Vaccine

Abstract

References (31)

Identification of an intestinal immune response using peripheral blood lymphocytes

Lancet

Antibody-secreting cells as a measure of the immunogenicity of an oral vaccine

Vaccine

Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation

Lancet

Efficacy of one or two doses of Ty21a Salmonella typhi vaccine in enteric-coated capsules in a controlled field trial

Vaccine

A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells

J. Immunol. Methods

A solid-phase immunoenzymatic technique for the enumeration of specific antibody-secreting cells

J. Immunol. Methods

Specific immunoglobulin-secreting human blood cells after peroral vaccination against Salmonella typhi

J. Infect. Dis.

IgA antibody-producing cells in peripheral blood after antigen ingestion: Evidence for a common mucosal immune system in humans

Immune response to acute diarrhea seen as circulating antibody-secreting cells

J. Infect. Dis.

Antibody secreting cells in acute urinary tract infection: indicator of local immune response possibly useful in localization of infection

Differentiation and migration of mucosal plasma cell precursors

Migration and regulation of B-cells in the mucosal immune system

Ann. NY Acad. Sci.

Cellular differentiation, migration, and function in the mucosal immune system

Antibody-secreting cell responses after vaccination with parenteral killed, oral killed and oral live vaccine

Comparison of the human immune response to live oral, killed oral or killed parenteral Salmonella typhi Ty21a vaccines

Microb. Pathog.

Cited by (47)

Novel pro-and eukaryotic expression plasmid expressing omicron antigens delivered via Salmonella elicited MHC class I and II based protective immunity

Bacteria-enabled oral delivery of a replicon-based mRNA vaccine candidate protects against ancestral and delta variant SARS-CoV-2

Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity

Correlates of protection for enteric vaccines

Typhoid Fever Vaccines

Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine

PaperDifferent profiles of the human immune response to primary and secondary immunization with an oral Salmonella typhi Ty21a vaccine

Abstract

Lancet

Vaccine

Lancet

Vaccine

J. Immunol. Methods

J. Immunol. Methods

Specific immunoglobulin-secreting human blood cells after peroral vaccination against Salmonella typhi

J. Infect. Dis.

IgA antibody-producing cells in peripheral blood after antigen ingestion: Evidence for a common mucosal immune system in humans

Immune response to acute diarrhea seen as circulating antibody-secreting cells

J. Infect. Dis.

Antibody secreting cells in acute urinary tract infection: indicator of local immune response possibly useful in localization of infection

Differentiation and migration of mucosal plasma cell precursors

Migration and regulation of B-cells in the mucosal immune system

Ann. NY Acad. Sci.

Cellular differentiation, migration, and function in the mucosal immune system

Antibody-secreting cell responses after vaccination with parenteral killed, oral killed and oral live vaccine

Comparison of the human immune response to live oral, killed oral or killed parenteral Salmonella typhi Ty21a vaccines

Microb. Pathog.

Paper
Different profiles of the human immune response to primary and secondary immunization with an oral Salmonella typhi Ty21a vaccine