Cellular and humoral responses to tetanus vaccination in gabonese children

doi:10.1016/j.vaccine.2008.04.067

Vaccine

Volume 26, Issues 29–30, 4 July 2008, Pages 3690-3695

https://doi.org/10.1016/j.vaccine.2008.04.067 Get rights and content

Abstract

Protection to tetanus is often not optimal in developing countries due to incomplete vaccination schemes, or decreased efficacy of vaccination. In this study we investigated the immunological response to tetanus booster vaccination in school children living in a semi-urban or in a rural area of Gabon. Tetanus-specific total IgG as well as antibody subclasses of the IgG1, IgG2, IgG3 and IgG4 isotype and the avidity of the dominating IgG1 subclass were determined both before and 1 month after the booster vaccination. In addition, tetanus-specific cytokine responses were determined. We found a polarization towards a T helper 1 (Th1) profile in the semi-urban children, whereas the cytokine responses of the rural children showed a T helper 2 (Th2) skewed response. Furthermore, tetanus-specific antibodies of the different IgG subclasses were all increased upon a tetanus booster vaccination and levels of IgG1 and IgG3 were higher in the rural children. In conclusion, a tetanus booster vaccination induced a stronger Th2 over Th1 cytokine profile to tetanus toxoid (TT) in rural children who showed the highest levels of IgG1 and IgG3 anti-TT antibody responses.

Introduction

Tetanus toxoid (TT) is a T cell dependent antigen and induces long-lasting immunity against tetanus. The immune response to TT vaccination has been extensively studied in populations in developed countries to show that protection is dependent on the amount of IgG antibodies, the subclass distribution, which is mainly dominated by IgG1, and the avidity of the produced antibodies [1]. Avidity is considered to be a parameter for the efficacy of the antibodies to neutralize the antigen as it reflects the collective functional affinities of the antibodies formed during a polyclonal humoral immune response [1]. Worldwide, TT vaccination has led to a greatly reduced morbidity and mortality associated with tetanus infection. However, efficacy can still be improved as long-term protection is often not established [2]. Moreover, exposure is still high in certain areas and therefore protection is very important [3]. Previous studies examining tetanus vaccination in developing countries have mostly investigated the effect that parasite infections might have on vaccination efficacy. Studies in onchocerciasis patients have shown that helminth infected subjects responded less efficiently to tetanus vaccination as defined by reduced IFN-γ production by T cells and/or reduced levels of antibodies [4], [5], [6]. In schistosomiasis the cytokine balance towards the tetanus vaccine was also shown to be skewed towards a Th2 response compared to a Th1 or Th0 response in uninfected controls, but no antibodies were measured in this study [7]. Moreover, earlier studies focused mainly on (young) adults.

In the current study the effect of booster vaccination with tetanus toxoid was investigated in children between 7 and 12 years of age in a rural and in a semi-urban area of Gabon to test the hypothesis that immune responses would be superior in semi-urban school children. The antibody responses in all IgG subclasses were determined and, in addition, the avidity of the IgG1 antibodies was examined to study the potential efficacy of the antibodies in neutralizing the antigen. Furthermore, the kinetics of in vitro antigen-induced cytokine responses after vaccination were analyzed.

Section snippets

Study cohort

The study was conducted in the vicinity of Lambaréné in Gabon, Central Africa. 131 children from Lambaréné, a semi-urban area and 120 children from the Nzilé rural area were examined for the presence of parasites. In the semi-urban area 19 percent of children were infected with Schistosoma haematobium versus 78 percent of the children in the rural area. In this study 33 children from the semi-urban area and 22 children of the rural area were vaccinated (Table 1). As the aim of the study was to

Study population

All study subjects in the rural area were infected with S. haematobium and 18 from the group of 20 were also infected with the intestinal helminths A. lumbricoides and/or Trichuris trichiuria (Table 1). These infections were less prevalent in the children in the semi-urban area (p < 0.001), where 13 out of 33 children were infected with S. haematobium and/or intestinal helminths. Plasmodium infections were found in 7 out of 20 rural and 4 out of 33 semi-urban children. In addition, the

Discussion

In this study we found higher levels of IgG1 anti-TT antibodies after vaccination of the rural children compared to the semi-urban children, although IgG1 avidity was not different amongst the groups. Further, the observation that IgG3 anti-TT was elevated in the rural subjects was unexpected, as IgG3 is mainly induced upon primary vaccination with protein antigens like TT [11]. High levels of IgG3 anti-TT were present in children that were found to have plasmodia infections during the study,

Acknowledgements

We thank the study participants in Gabon for volunteering in this study, Ludovic Mewono and Ghyslain Mombo Ngoma for collecting samples on day 28, Nestor Obiang, Brigitte Mingombet and Bart Everts for their technical assistance and all workers in the Albert Schweitzer Hospital for their hospitality and cooperation. Further we thank Revelino Vieira for performing the cytokine measurements and Anja Jansen-Hoogendijk for performing the tetanus serology. This work was supported by the Dutch

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Helminth parasites infect more than a quarter of the human population and inflict significant changes to the immunological status of their hosts. Several human studies report impaired responses to vaccinations in helminth-infected individuals. Analysing the impact of helminth infections on the efficacy of influenza vaccinations in the mouse system helps to elucidate the underlying immunological processes. Concurrent infection with the parasitic nematode Litomosoides sigmodontis reduced the quantity and quality of antibody responses to vaccination against seasonal influenza in BALB/c and C57BL/6 mice. This led to impaired vaccination-induced protection against challenge infections with the human pathogenic 2009 pandemic H1N1 influenza A virus in helminth-infected mice. Impaired responses were also observed if vaccinations were performed after immune-driven or drug-induced clearance of a previous helminth infection. Mechanistically, the suppression was associated with a systemic and sustained expansion of IL-10-producing CD4⁺CD49b⁺LAG-3⁺ type 1 regulatory T cells and partially abrogated by in vivo blockade of the IL-10 receptor. In summary, these findings raise the concern that individuals in helminth-endemic areas may not always benefit from vaccinations, even in the absence of an acute and diagnosable helminth infection.
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The respective vaccines are among the most frequently administered vaccines worldwide and are well-understood in terms of their effectiveness and patient safety (ECDC, 2009; Weinberger, 2016). Examining ATX concentrations provides information on the patient’s immune response and thus on the effectiveness of the immunization program (van Riet et al., 2008; Weinberger, 2016). At the same time, it serves as a way to assess immune response in individuals with a suspected immunodeficiency (Farmand et al., 2017; Blauvelt et al., 2019).
The aim of this study was to evaluate the development and status quo of the quality of high throughput in vitro diagnostic testing for tetanus and diphtheria antitoxin antibody (ATX) concentrations based on external quality assessment (EQA) data.
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While the results were mostly well aligned, individual surveys showed widely dispersed ATX concentrations. The medians of manufacturer collectives deviated from the overall median by up to 8.9-fold in the case of diphtheria ATX and by up to 3.5-fold in the case of tetanus ATX. Such a distribution in the results is particularly critical in the cut-off range for immunity and may lead to an incorrect assessment of vaccination status.
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Urban-rural differences in immune responses to mycobacterial and tetanus vaccine antigens in a tropical setting: A role for helminths?
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Some enteric vaccines also show variable efficacy between low- and high-income countries [8,9]. In the tropics, rural settings appear more affected [10–13]. For example, influenza and tetanus vaccine responses have been shown to be lower in rural compared to urban Gabon [12,13].
Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1–17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-γ and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-γ, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response.
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¹: Current address: Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands.

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Vaccine

Abstract

Introduction

Section snippets

Study cohort

Study population

Discussion

Acknowledgements

References (20)

Tetanus antibody levels among adolescent girls in developing countries

Trans R Soc Trop Med Hyg

Antibody avidity determination by ELISA using thiocyanate elution

J Immunol Methods

Titers of antibody to common pathogens: relation to food-based interventions in rural Kenyan schoolchildren

Am J Clin Nutr

Immunity to blood stages of Plasmodium falciparum is dependent on a specific pattern of immunoglobulin subclass responses to multiple blood stage antigens

Med Hypotheses

Immunoglobulin G (IgG) subclass distribution and IgG1 avidity of antibodies in human immunodeficiency virus-infected individuals after revaccination with tetanus toxoid

Clin Diagn Lab Immunol

Factors affecting the immunogenicity and potency of tetanus toxoid: implications for the elimination of neonatal and non-neonatal tetanus as public health problems

Bull World Health Organ

Response to tetanus immunization in onchocerciasis patients

Ann Trop Med Parasitol

Human onchocerciasis and tetanus vaccination: impact on the postvaccination antitetanus antibody response

Infect Immun

Impaired tetanus-specific cellular and humoral responses following tetanus vaccination in human onchocerciasis: a possible role for interleukin-10

J Infect Dis

Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni

J Infect Dis

Cited by (36)

Infants can access Ebola vaccines in during outbreaks

Filarial infections compromise influenza vaccination efficacy: Lessons from the mouse

Evaluation of INSTAND e.V.’s external proficiency testing program for tetanus and diphtheria antitoxin detection: Lessons for assessing levels of immunoprotection

Urban-rural differences in immune responses to mycobacterial and tetanus vaccine antigens in a tropical setting: A role for helminths?

Reduced antibody responses against Plasmodium falciparum vaccine candidate antigens in the presence of Trichuris trichiura

Reactivated and clinical Toxoplasma gondii infection in young lambs: Clinical, serological and pathological evidences