Acceptance and uptake of vaccines against tetanus, influenza, pertussis, and COVID-19 among pregnant and postpartum women in low- and middle-income countries: a systematic review and meta-analysis protocol.

BACKGROUND: Pregnant women, fetuses, and neonates are particularly vulnerable to vaccine-preventable diseases (VPDs). These VPDs are associated with high morbidity and mortality among expectant mothers and their fetuses and neonates. Vaccination during pregnancy can protect the expectant mother from VPDs to which she may be especially vulnerable while pregnant. In addition, the passive transfer of maternal neutralizing immunoglobulin G (IgG) and secretory immunoglobulin A (IgA) also protects the fetus against congenital infections and may further protect the neonate from infection during the first few months of life. Despite this, coverage of recommended maternal vaccines remains suboptimal globally, especially in resource-constrained settings. Determinants of vaccine acceptance and uptake are frequently understudied in low- and middle-income countries (LMICs) and among specific groups such as pregnant and postpartum women. This proposed systematic review will assess the acceptance and uptake of vaccines against tetanus, influenza, pertussis, and COVID-19 among pregnant and postpartum women in LMICs. METHODS: A Boolean search strategy employing common and medical subject heading (MeSH) terms for tetanus, influenza, pertussis, and COVID-19 vaccines, as well as vaccine acceptance, hesitancy, together with uptake, pregnancy, and postpartum, will be used to search electronic databases for relevant literature published between 2009 and 2024. Only studies conducted in LMICs that investigated determinants of acceptance, hesitancy, and uptake of tetanus, influenza, pertussis, and COVID-19 vaccines among pregnant and postpartum women will be eligible for inclusion in the review. The quality and the risk of bias of all eligible full-text articles will be assessed using the Joanna Briggs Institute's (JBI) critical appraisal tools. DISCUSSION: This protocol proposes a systematic review and meta-analysis that aims to assess the uptake of maternal vaccines and to systematically appraise and quantify determinants of the acceptance and uptake of recommended vaccines during pregnancy and postpartum in LMICs. A better understanding of these factors and how they influence maternal vaccine decision-making will enable public health practitioners as well as global and national policymakers to design more effective interventions as we look towards expanding the scope and reach of maternal immunization programs.

Seroprotection against tetanus in HIV-exposed and HIV-unexposed infants in Malawi in 2019-2020.

In Malawi, tetanus toxoid vaccination (TTV) is recommended in pregnancy, but few studies have assessed the prevalence of infant seroprotection against tetanus. Anti-TT levels from 84 6-week-old infants, born in 2019-2020 to mothers living with HIV (HEU: HIV-exposed-uninfected) infants and to HIV-negative women (HUU: HIV-unexposed-uninfected) infants were determined by ELISA assay. Although 94% of the infants (HEU=94.8%, HUU=92.3%) showed protective levels (>0.1 IU/mL), the mean titers observed (0.51 IU/mL) suggest an incomplete compliance with TT vaccination. The only factor positively correlated to anti-TT IgG levels was the duration of maternal antiretroviral therapy in HEU.

Phase 1 trial of an investigational Tdap booster vaccine with CpG 1018 adjuvant compared with Boostrix in healthy adults and adolescents.

This phase 1 trial assessed the safety and immunogenicity of an investigational tetanus/diphtheria/acellular pertussis vaccine combined with CpG 1018 adjuvant 1500 µg (Tdap-1018 1500 µg) or 3000 µg (Tdap-1018 3000 µg) in adults and adolescents. In this randomized, active-controlled, multicenter, dose-escalation trial, healthy participants aged 10 to 22 years received 1 dose of Tdap-1018 1500 µg, Tdap-1018 3000 µg, or Boostrix. Geometric mean concentrations (GMCs) and booster response rates (BRRs) for antibodies against pertussis (pertussis toxin, filamentous hemagglutinin, pertactin), tetanus, and diphtheria antigens, and neutralizing antibodies against pertussis toxin were assessed 4 weeks after vaccination. Safety and tolerability were assessed for solicited post-injection reactions within 7 days after vaccination and unsolicited adverse events up to 12 weeks after vaccination. Of 117 enrolled participants, 80 adults (92%) and 30 adolescents (100%) completed the study. Both Tdap-1018 formulations were generally well tolerated, with no vaccine-related serious adverse events. Frequency and severity in post-injection reactions after Tdap-1018 administration were similar to Boostrix except for higher proportions of moderate pain for Tdap-1018. In adults at week 4, ratio of GMCs and BRRs for all antigens in the 3000-µg group were similar to or higher than Boostrix, with significantly higher GMC ratios for anti-pertussis toxin (2.1 [1.5-3.0]) and anti-tetanus (1.8 [1.1-2.9]) and significantly higher BRRs for anti-pertussis toxin (difference [95% CI]: 34.5% [13.4-54.6]), anti-pertactin (19.2% [4.4-38.1]), and anti-tetanus (30.0% [3.6-52.7]) antibodies. For adolescents, in the 3000-µg group, ratio of GMCs and BRRs were similar to or higher than Boostrix for all antigens. Both Tdap-1018 formulations showed acceptable safety and tolerability profiles. Tdap-1018 3000 µg induced similar or higher immune responses than Boostrix. ACTRN12620001177943 (Australian New Zealand Clinical Trials Registry; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12620001177943p).

Seroprevalence of IgG antibodies against tetanus toxoid among different age groups in Poland.

INTRODUCTION AND OBJECTIVE: Vaccination is the most effective and reliable strategy for preventing the morbidity of tetanus. The aim of the study is to investigate the seroprevalence of antibodies to tetanus toxoid among healthy persons across all age groups to determine the level of vaccine-induced immunity in the population, and to identify which age group should be targeted for a booster dose. MATERIAL AND METHODS: A total of 2,842 serum samples collected between 2010 - 2019 from individuals aged from 1 month - 97 years were investigated. Anti-tetanus IgG antibody concentrations (IU/ml) were measured by an enzyme-linked immunosorbent assay. In addition, the avidity of antibodies was determined using an in-house ELISA. RESULTS: The results showed that among the 2,842 individuals, 147 (5.2%) had anti-tetanus toxoid IgG antibody levels below 0.1 IU/ml and another 1,519 (53.4%) subjects showed only basic protection (0.1-1.0 IU/ml) and needed immediate booster. High levels of anti-tetanus toxoid IgG antibodies (>1.0 IU/ml) were found more often in young adults at the age 21-40 years (55.5%, GMT=1.15). Importantly, these antibodies also had the highest avidity. With age, the percentage of high positives decreased, as well as the geometric mean and avidity of antibodies, reaching the lowest level in subjects over 70 years of age (13.3%; GMT=0.19). Characteristically, a higher percentage of high positive results was observed in men (42.6%) than in women (34.3%). CONCLUSIONS: The study showed adequate immunity levels to tetanus amongst the Polish population, especially in children, adolescents, and young adults. However, those from older age groups should receive booster doses of the vaccine.

Collaborative study for the characterisation of the BINACLE Assay for in vitro detection of tetanus toxicity in toxoids - Part 2.

Tetanus vaccines for human and veterinary use are produced by formaldehyde-induced inactivation of tetanus neurotoxin (TeNT) purified from Clostridium tetani cultures. Due to the high morbidity caused by exposure to TeNT it is essential that the quality control of tetanus vaccines includes testing for absence of tetanus toxin as prescribed by European Pharmacopoeia monographs 0452 and 0697. Currently this test is carried out in guinea pigs for each bulk of tetanus toxoid. To test the applicability of the in vitro BINACLE ("binding and cleavage") assay as an alternative method for the quality control of tetanus vaccines, two collaborative studies were run by the European Directorate for the Quality of Medicines & HealthCare under the aegis of the Biological Standardisation Programme. The first collaborative study indicated that the method allows sensitive TeNT detection. However, a clear conclusion could not be drawn due to the high variability of the results. To address the variability, the protocol was optimised and further standardised for the second study. The study results demonstrated good assay precision, both with respect to repeatability and reproducibility. Importantly, the limit of detection was 0.11 ng/mL TeNT in five out of nine laboratories and 0.33 ng/mL in four out of nine laboratories, suggesting that the BINACLE assay can detect TeNT with similar sensitivity as in vivo toxicity tests and can thus be taken into consideration as an alternative method to the current compendial in vivo test.

Collaborative study for the characterisation of the BINACLE Assay for in vitro detection of tetanus toxicity in toxoids - Part 1.

For several decades the European Pharmacopoeia monographs Tetanus vaccine (adsorbed) (0452) and Tetanus vaccine for veterinary use (0697) required that Specific toxicity and Absence of toxin and irreversibility of the toxoidof each bulk of tetanus toxoids had to be tested by an in vivo toxicity test in guinea pigs before it could be included in vaccines for human or veterinary use. In line with the 3Rs concept of replacing, reducing and refining animal experiments, an in vitro method for the detection of active tetanus neurotoxin (TeNT) has been developed at the Paul-Ehrlich-Institut (PEI, Germany). This method, the so-called BINACLE (binding and cleavage) assay, uses the receptor-binding and proteolytic properties of TeNT for the specific detection of active toxin molecules. Successful in-house validation studies as well as a small-scale transferability study had demonstrated that this method may represent a suitable alternative to the compendial in vivo toxicity test. As a follow up, an international collaborative study aimed at verifying the suitability of the BINACLE assay as a potential alternative to the guinea pig toxicity test for tetanus toxoids was organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM) under the aegis of its Biological Standardisation Programme (BSP). Within the framework of this study, coded BSP136, a feasibility phase - also referred to as Phase 1 - was run to select and qualify critical study reagents and samples and to assess the performance of the BINACLE Standard Operating Procedure developed by the project leaders. Then the international collaborative study aimed at evaluating the BINACLE, referred to as BSP136 Phase 2, was started. A total of 19 international laboratories (comprising vaccine manufacturers as well as national control laboratories) were supplied with a detailed assay protocol, critical reagents required for the assay, three samples consisting of three different bulk tetanus toxoids donated by major European vaccine manufacturers and one international standard toxoid. Each of the participants was asked to perform three independent BINACLE assays following the provided protocol. The statistical analysis of the results showed that most of the participating laboratories were able to perform the BINACLE assay according to the provided protocol. However, the results obtained by the participants varied widely, and not all the laboratories were able to achieve a sensitive detection of active TeNT. Multiple factors may have contributed to the elevated variability of the BSP136 study results. From an analysis of these factors, strategies were developed to help increase the standardisation of the BINACLE assay and obtain more consistent results in a follow-up validation study, BSP 136 Phase 3 (Part 2), for which the experimental phase took place in 2023. The present manuscript summarises the outcome of Phases 1 and 2, which constitute Part 1 of the BSP136 project.

Evaluation of interventions to improve timely hepatitis B birth dose vaccination among infants and maternal tetanus vaccination among pregnant women in Nigeria.

BACKGROUND: Nigeria has the largest number of children infected with hepatitis B virus (HBV) globally and has not yet achieved maternal and neonatal tetanus elimination. In Nigeria, maternal tetanus diphtheria (Td) vaccination is part of antenatal care and hepatitis B birth dose (HepB-BD) vaccination for newborns has been offered since 2004. We implemented interventions targeting healthcare workers (HCWs), community volunteers, and pregnant women attending antenatal care with the goal of improving timely (within 24 hours) HepB-BD vaccination among newborns and Td vaccination coverage among pregnant women. METHODS: We selected 80 public health facilities in Adamawa and Enugu states, with half intervention facilities and half control. Interventions included HCW and community volunteer trainings, engagement of pregnant women, and supportive supervision at facilities. Timely HepB-BD coverage and at least two doses of Td (Td2+) coverage were assessed at baseline before project implementation (January-June 2021) and at endline, one year after implementation (January-June 2022). We held focus group discussions at intervention facilities to discuss intervention strengths, challenges, and improvement opportunities. RESULTS: Compared to baseline, endline median vaccination coverage increased for timely HepB-BD from 2.6% to 61.8% and for Td2+ from 20.4% to 26.9% in intervention facilities (p < 0.05). In comparison, at endline in control facilities median vaccination coverage for timely HepB-BD was 7.9% (p < 0.0001) and Td2+ coverage was 22.2% (p = 0.14). Focus group discussions revealed that HCWs felt empowered to administer vaccination due to increased knowledge on hepatitis B and tetanus, pregnant women had increased knowledge that led to improved health seeking behaviors including Td vaccination, and transportation support was needed to reach those in far communities. CONCLUSION: Targeted interventions significantly increased timely HepB-BD and Td vaccination rates in intervention facilities. Continued support of these successful interventions could help Nigeria reach hepatitis B and maternal and neonatal tetanus elimination goals.

Progress Toward Achieving and Sustaining Maternal and Neonatal Tetanus Elimination - Worldwide, 2000-2022.

Tetanus remains a considerable cause of mortality among undervaccinated mothers and their infants following unhygienic deliveries, especially in low-income countries. Strategies of the maternal and neonatal tetanus elimination (MNTE) initiative, which targets 59 priority countries, include strengthening antenatal immunization of pregnant women with tetanus toxoid-containing vaccines (TTCVs); conducting TTCV supplementary immunization activities among women of reproductive age in high-risk districts; optimizing access to skilled birth attendants to ensure clean deliveries and umbilical cord care practices; and identifying and investigating suspected neonatal tetanus cases. This report updates a previous report and describes progress toward MNTE during 2000-2022. By December 2022, 47 (80%) of 59 priority countries were validated to have achieved MNTE. In 2022, among the 50 countries that reported coverage with ≥2 doses of TTCV among pregnant women, 16 (32%) reported coverage of ≥80%. In 2022, among 47 validated countries, 26 (55%) reported that ≥70% of births were assisted by skilled birth attendants. Reported neonatal tetanus cases worldwide decreased 89%, from 17,935 in 2000 to 1,995 in 2021; estimated neonatal tetanus deaths decreased 84%, from 46,898 to 7,719. However, the global disruption of routine immunization caused by the COVID-19 pandemic impeded MNTE progress. Since 2020, reported neonatal tetanus cases have increased in 18 (31%) priority countries. Integration of MNTE strategies into priority countries' national postpandemic immunization recovery activities is needed to achieve and sustain global elimination.

Bacillus toyonensis amplifies the immunogenicity of an experimental recombinant tetanus vaccine in horses.

Probiotic microorganisms can stimulate an immune response and increase the efficiency of vaccines. For example, Bacillus toyonensis is a nonpathogenic, Gram-positive bacterium that has been used as a probiotic in animal supplementation. It induces immunomodulatory effects and increases the vaccine response in several species. This study aimed to evaluate the effect of B. toyonensis supplementation on the modulation of the immune response in horses vaccinated with recombinant Clostridium tetani toxin. Twenty horses were vaccinated twice, with an interval of 21 days between doses, and equally divided into two groups: the first group was supplemented orally for 42 days with feed containing viable spores of B. toyonensis (1 × 108) mixed with molasses (40 ml), starting 7 days before the first vaccination; the second (control) group received only feed mixed with molasses, starting 7 days before the first vaccination. Serum samples were collected to evaluate the humoral immune response using an in-house indirect enzyme-linked immunosorbent assay (ELISA), and peripheral blood mononuclear cells (PBMCs) were collected to evaluate cytokine transcription (qPCR). For the specific IgG-anti-rTENT titer, the supplemented group had ELISA values that were four times higher than those of the control group (p < 0.05). The supplemented group also showed higher ELISA values for the IgGa and IgGT sub-isotypes compared to the control group. In PBMCs stimulated with B. toyonensis, relative cytokine transcription of the supplemented group showed 15-, 8-, 7-, and 6-fold increases for IL1, TNFα, IL10 and IL4, respectively. When stimulated with a vaccine antigen, the supplemented group showed 1.6-, 1.8-, and 0.5-fold increases in IL1, TNFα, and IL4, respectively, compared to the control group. Horses supplemented with B. toyonensis had a significantly improved vaccine immune response compared to those in the control group, which suggests a promising approach for improving vaccine efficacy with probiotics.

Local Tetanus Begins with a Neuromuscular Junction Paralysis around the Site of Tetanus Neurotoxin Release due to Cleavage of the Vesicle-Associated Membrane Protein.

Local tetanus develops when limited amounts of tetanus neurotoxin (TeNT) are released by Clostridium tetani generated from spores inside a necrotic wound. Within days, a spastic paralysis restricted to the muscles of the affected anatomical area develops. This paralysis follows the retrograde transport of TeNT inside the axons of motoneurons and its uptake by inhibitory interneurons with cleavage of a vesicle-associated membrane protein required for neurotransmitter release. Consequently, incontrollable excitation of motoneurons causes contractures of innervated muscles and leads to local spastic paralysis. Here, the initial events occurring close to the site of TeNT release were investigated in a mouse model of local tetanus. A peripheral flaccid paralysis was found to occur, before or concurrent to the spastic paralysis. At variance from the confined TeNT proteolytic activity taking place within motor neuron terminals, central protein cleavage was detected within inhibitory interneurons controlling motor neuron efferents innervating muscle groups distant from the site of TeNT release. These results indicate peripheral activity of TeNT in tetanus and explains why the spastic paralysis observed in local tetanus, although confined to single limbs, generally affects multiple muscles. The initial TeNT neuroparalytic activity can be detected by measuring the compound muscle action potential, providing a very early diagnosis and therapy, thus preventing the ensuing life-threatening generalized tetanus.

A Dual Strategy-In Vitro and In Silico-To Evaluate Human Antitetanus mAbs Addressing Their Potential Protective Action on TeNT Endocytosis in Primary Rat Neuronal Cells.

Tetanus disease, caused by C. tetani, starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic treatment in case of accidents. The incidence of tetanus is high in underdeveloped countries, requiring the administration of antitetanus antibodies, usually derived from immunized horses or humans. Heterologous sera represent risks such as serum sickness. Human sera can carry unknown viruses. In the search for human monoclonal antibodies (mAbs) against TeNT (Tetanus Neurotoxin), we previously identified a panel of mAbs derived from B-cell sorting, selecting two nonrelated ones that binded to the C-terminal domain of TeNT (HCR/T), inhibiting its interaction with the cellular receptor ganglioside GT1b. Here, we present the results of cellular assays and molecular docking tools. TeNT internalization in neurons is prevented by more than 50% in neonatal rat spinal cord cells, determined by quantitative analysis of immunofluorescence punctate staining of Alexa Fluor 647 conjugated to TeNT. We also confirmed the mediator role of the Synaptic Vesicle Glycoprotein II (SV2) in TeNT endocytosis. The molecular docking assays to predict potential TeNT epitopes showed the binding of both antibodies to the HCR/T domain. A higher incidence was found between N1153 and W1297 when evaluating candidate residues for conformational epitope.

[Expert consensus on the use of tetanus vaccines for the high-risk group of post-traumatic tetanus].

Tetanus remains a potentially fatal disease with highly severe consequences worldwide. China has eliminated neonatal tetanus since 2012, but post-traumatic tetanus still represents a substantial public health burden. It is of great significance to implement active pre-exposure immunization among the high-risk group of post-traumatic tetanus in China, which can help reduce the burden of post-traumatic tetanus. Based on the World Health Organization's position paper on tetanus vaccines and relevant regulations and standards issued by China. This consensus introduces the pre-exposure immunization prevention strategies for tetanus both domestically and internationally, as well as the definition of a high-risk group of post-traumatic tetanus in China. It also provides recommendations on using active immunological preparation for tetanus, which can be used as a reference for relevant personnel engaged in disease prevention, control, and vaccination.

Characterization of neutralizing chimeric heavy-chain antibodies against tetanus toxin.

Tetanus toxin (TeNT) is one of the most toxic proteins. Neutralizing antibodies against TeNT are effective in prevention and treatment. In this study, 14 anti-tetanus nanobodies were obtained from a phage display nanobody library by immunizing a camel with the C-terminal receptor-binding domain of TeNT (TeNT-Hc) as the antigen. After fusion with the human Fc fragment, 11 chimeric heavy-chain antibodies demonstrated nanomolar binding toward TeNT-Hc. The results of toxin neutralization experiments showed that T83-7, T83-8, and T83-13 completely protected mice against 20 × the median lethal dose (LD50) at a low concentration. The neutralizing potency of T83-7, T83-8, and T83-13 against TeNT is 0.4 IU/mg, 0.4 IU/mg and 0.2 IU/mg, respectively. In the prophylactic setting, we found that 5 mg/kg of T83-13 provided the mice with full protection from tetanus, even when they were injected 14 days before exposure to 20 × LD50 TeNT. T83-7 and T83-8 were less effective, being fully protective only when challenged 7 or 10 days before exposure, respectively. In the therapeutic setting, 12 h after exposure to TeNT, 1 ~ 5 mg/kg of T83-7, and T83-8 could provide complete protection for mice against 5 × LD50 TeNT, while 1 mg/kg T83-13 could provide complete protection 24 h after exposure to 5 × LD50 TeNT. Our results suggested that these antibodies represent prophylactic and therapeutic activities against TeNT in a mouse model. The T83-7, T83-8, and T83-13 could form the basis for the subsequent development of drugs to treat TeNT toxicity.

Antibody levels following vaccination of beef calves with a tetanus toxoid.

Tetanus is a preventable, yet often fatal, disease affecting many species, including beef cattle. Vaccination for tetanus is recommended for calves at high risk of disease, but typical beef cattle management practices often make adherence to vaccine manufacturers' guidance for a second (booster) dose of vaccine difficult. This study examined the antibody response following a single dose of tetanus toxoid, as well as following booster vaccination at various intervals. Anti-tetanus IgG antibodies were detectable 25 days (D25) after a single dose, and rose following booster at either D25 D109 after initial vaccination. Antibody levels then declined numerically from D109 to D179 for calves boostered at D25 but rose on D179 for those receiving a second dose on D109. The relatively rapid response in IgG production, even in the absence of a booster vaccine, may suggest value in vaccinating calves for tetanus at time of greatest risk, even if a booster cannot be administered. The study also provides support for priming of the immune response lasting at least until D109 after primary immunization.

Tetanus prophylaxis in horses: guidelines for New Zealand and Australia based on a critical appraisal of the evidence.

Horses are exquisitely sensitive to tetanus neurotoxin and are exposed to the risk of infection with Clostridium tetani throughout life. The vaccine against tetanus is highly effective at preventing disease, whereas tetanus in unvaccinated populations is associated with high mortality rates. Current guidelines in New Zealand and Australia for the available vaccine contain contradictions and limitations surrounding the optimal tetanus immunisation protocols for both adult horses and foals. This review critically evaluates the scientific literature on tetanus prophylaxis in horses within the context of equine practice and available products in New Zealand and Australia. The review was conducted by a panel of industry and specialist veterinarians to obtain agreement on nine equine tetanus prophylaxis guidelines for practising veterinarians. The primary protocol for tetanus toxoid (TT) immunisation consists of a three-dose series IM for all horses ≥ 6 months of age, and a four-dose series IM is proposed if commencing vaccination in foals between 3 and 6 months of age. Tetanus prophylaxis in foals < 3 months of age relies on passive immunity strategies. Following the completion of the primary protocol, a TT booster dose IM should be administered within 5 years, and every 5 years thereafter. When followed, these protocols should provide adequate protection against tetanus in horses. Additional tetanus prophylaxis guidelines are provided for veterinarians attending a horse experiencing a known "risk event" (e.g. wound, hoof abscess, surgery, umbilical infection). When a correctly vaccinated horse experiences a risk event, pre-existing immunity provides protection against tetanus. When an unvaccinated horse or one with unknown vaccination status, or a foal born to an unvaccinated dam, experiences a risk event, TT IM and tetanus antitoxin (TAT) 1,500 IU SC should be administered simultaneously at separate sites, and the TT primary immunisation protocol should subsequently be completed for the horse's respective age. In previously immunised pregnant broodmares, a TT booster dose administered 4-8 weeks prior to parturition optimises the transfer of passive immunity against tetanus to the newborn foal via colostrum; provided that post-natal IgG concentration in serum is > 800 mg/dL (8 g/L), such foals should be passively protected against tetanus up to 6 months of age. Survivors of clinical tetanus must still receive the primary protocol for vaccination against tetanus. In summary, all horses in New Zealand and Australia should be vaccinated against tetanus with protection maintained throughout life via TT booster doses, facilitated by accurate medical record keeping and client education.