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.

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.

[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.

Management of severe tetanus in Afghanistan: lessons from the field.

INTRODUCTION: Tetanus is a rather rare disease in the Western countries thanks to widespread vaccination programs and the availability of prophylactics for patients with tetanus-prone injuries. The few cases that do occur are promptly managed in intensive care units (ICUs). However, tetanus is not so rare in developing countries, where access to a suitable level of care is limited. An unstable political situation can be a significant factor influencing patient outcomes. CASE REPORT: A ten-year-old boy presented at the EMERGENCY hospital in Lashkar-Gah (southern Afghanistan) with generalized tetanus after falling off his bicycle. In response to his rapidly deteriorating general conditions - respiratory failure and hemodynamic instability - the patient was urgently transferred by ambulance to the ICU at the EMERGENCY hospital in Kabul (northern Afghanistan). The patient was placed on mechanical ventilation while receiving intravenous sedation and pharmacologic paralysis for almost four weeks. A prolonged infusion of a high dose of magnesium sulphate and labetalol was also given to counteract autonomic dysfunction. Multiple complications related to the long stay in the ICU were observed and promptly addressed. During this period, several mass casualties took place in Kabul, which stretched the hospital's surge capacity. The patient was discharged and accompanied back to Lashkar-Gah three months after his admission to the hospital. CONCLUSION: This case report shows some of the many difficulties that arise when managing a patient with severe tetanus in a war zone where resources are limited.

Number of tetanus toxoid injections before birth and associated factors among pregnant women in low and middle income countries: Negative binomial poisson regression.

BACKGROUND: In low- and middle-income countries where vaccination rates are low, tetanus is still an important threat to public health. Although maternal and neonatal tetanus remains a major global health concern, its magnitude and determinates are not well studied. Therefore, this study aimed to assess the number of tetanus toxoid injections and associated factors among pregnant women in low- and middle-income countries. METHODS: Data from the most recent Demographic and Health Surveys, which covered 60 low- and middle-income countries from 2010 to 2022, was used for secondary data analysis. The study included a total of 118,704 pregnant women. A statistical software package, STATA 14, was used to analyze the data. A negative binomial regression of a cross-sectional study was carried out. Factors associated with the number of tetanus vaccinations were declared significant at a p-value of < 0.05. The incidence rate ratio and confidence interval were used to interpret the results. A model with the smallest Akaike Information Criterion and Bayesian Information Criterion values and the highest log likelihood was considered the best-fit model for this study. RESULTS: In low- and middle-income countries, 26.0% of pregnant women took at least two doses of the tetanus toxoid vaccine. Factors such as maternal education, primary (IRR = 1.22, 95% CI: 1.17, 1.26), secondary (IRR = 1.19, 95% CI: 1.15, 1.23), higher (IRR = 1.16, 95% CI: 1.12, 1.20), employment (IRR = 1.11, 95% CI: 1.09, 1.13), 1-3 ANC visits (IRR = 2.49, 95% CI: 2.41, 2.57), ≥4 visits (IRR = 2.94, 95% CI: 2.84, 3.03), wealth index (IRR = 1.06; 95% CI: 11.04, 1.08), ≥birth order (IRR = 1.04, 95% CI: 1.02, 1.27), distance to health facility (IRR = 1.02, 95% CI: 1.00, 1.03), and health insurance coverage (IRR = 1.08; 95% CI: 1.06, 1.10) had a significant association with the number of tetanus vaccinations among pregnant women. CONCLUSIONS AND RECOMMENDATIONS: This study concludes that the number of tetanus toxoid vaccinations among pregnant women in low- and middle-income countries is low. In the negative binomial model, the frequency of tetanus vaccinations has a significant association with maternal employment, educational status, wealth index, antenatal care visits, birth order, distance from a health facility, and health insurance. Therefore, the ministries of health in low and middle-income countries should give attention to those women who had no antenatal care visits and women from poor wealth quantiles while designing policies and strategies.

Prolonged administration of intrathecal baclofen in a patient with generalized grade 4 tetanus.

INTRODUCTION: This case report presents the management of a 62-year-old woman with generalized grade 4 tetanus, focusing on the innovative use of intrathecal baclofen (ITB) therapy. The patient initially presented with a laceration and subsequently developed severe tetanic spasms, necessitating interventions beyond standard tetanus immunoglobulin and antibiotics due to the condition's progressive and life-threatening nature. The preference for ITB over oral baclofen is highlighted, considering ITB's enhanced bioavailability in the central nervous system and its efficacy in reducing spinal cord reflexes, which is critical for managing severe spasticity.On her return to the emergency department with symptoms of tetanus, the patient received ITB following the failure of oral baclofen to control the spasms. ITB administration necessitated a lumbar drain, which was later substituted with a tunneled intrathecal catheter due to the extended requirement for baclofen infusion and the unavailability of suitable infusion pumps. This scenario represented a significant application of a CADD-Solis external pump for continuous ITB infusion.Transitioning the patient from ITB to oral baclofen was a crucial management step to facilitate discharge and recovery, underscoring the importance of a careful approach to prevent withdrawal symptoms and maintain care continuity. Despite initial complications, including an infection signaled by leucocytosis and confirmed through cerebrospinal fluid culture, the patient was effectively treated and discharged. CONCLUSION: This report contributes to the sparse literature on prolonged ITB use for generalized grade 4 tetanus treatment, underlining the need for interdisciplinary collaboration for the best patient outcomes. It showcases the potential of ITB in spasticity management, in reducing the need for sedation, and in shortening the duration of mechanical ventilation, advocating for a tailored approach that utilizes a full spectrum of pharmacological and supportive therapies.

Seroprotection against tetanus in the Italian general population.

BACKGROUND: Tetanus is a non-communicable disease, preventable with vaccination. Despite the implemented vaccination strategy, a certain number of tetanus cases per year continue to occur. The aim of the study was to evaluate the seroprevalence of anti-tetanus antibodies in the Italian population by age, sex and geographical area. METHODS: To determine the level of tetanus-specific antibodies, an immunoenzymatic assay was used. RESULTS: A total of 3,821 serum samples were collected in the years 2019-20 from healthy subjects aged 6-90 years residing in 13 Italian regions. Overall, 85 % of the tested subjects resulted positive. The rate of subjects protected against tetanus showed a gradual decrease from the younger age groups to the older ones (6-12 years: 93.6 %, 13-24 years: 91.8 %, 25-39 years: 91.0 %, 40-64 years: 78.2 %, ≥ 65 years: 45.3 %); this is particularly evident in the Southern regions and Islands. Moreover, the prevalence of subjects with low protection (<0.1 IU/ml) was significantly higher in the ≥ 65 age group (10.3 %). Males and females' prevalence showed a significant difference only in the oldest age group (M: 60.8 %, F: 30.4 %). In general, a higher prevalence was observed for Northern (90.8 %) and Central regions (87.3 %) than Southern regions and Islands (80.0 %). CONCLUSION: These data, compared with epidemiological ones which showed a high number of cases in the elderly, confirmed that the population with lower protection has a greater risk of contracting the disease, demonstrating the need for adequate immunization through both primary vaccination and boosters for all ages and both sexes, in order to provide lifelong protection.

Acute Muscle Rigidity Secondary to Tetanus: A Toxicology Simulation Case for Fourth-Year Medical Students.

Introduction: Tetanus is uncommon in the United States secondary to vaccination. However, vaccination hesitancy is increasing. This case challenges medical students to consider tetanus in the differential and understand its complications. Methods: Fourth-year medical students took a pretest on the neurotransmitter glycine and associated disease states. They received two 10-minute lectures on glycine and acid-base abnormalities. Students then participated in a simulation featuring a 27-year-old man bitten by a dog, resulting in tetanus. Required equipment included a mannequin with monitor, a defibrillator, and personal protective equipment. Critical actions consisted of learners dividing up roles amongst each other, using closed-loop communication, placing the patient on a cardiac monitor, choosing to establish IV access and intubate the patient, starting IV fluids, and administering tetanus immunoglobulin. The case ended after 20 minutes. Outcome measurements encompassed performance on a posttest and critical actions. Results: Twenty students participated. Mean pretest and posttest scores were 69.5 and 92.5, respectively (p < .001). All groups completed the items on the critical actions checklist within a 20-minute time frame. Discussion: Rising vaccine hesitancy may increase the likelihood of physicians encountering new cases of tetanus and require them to perform lifesaving management of a patient presenting with muscle rigidity. This simulation provides learners with hands-on experience caring for a patient with tetanus and muscle rigidity. It can improve their knowledge of recognition, assessment, and decision-making toward lifesaving management of tetanus by allowing them to practice their skills in a safe environment.

Immunogenicity and safety of adsorbed diphtheria-purified pertussis-tetanus-inactivated polio (Sabin strain)-Haemophilus type b conjugate combined vaccine (DPT-IPV-Hib) in healthy Japanese Infants ≥ 2 and < 43 months of Age: A phase III, multicenter, active controlled, assessor-blinded, randomized, parallel-group study.

OBJECTIVE: This study investigated the immunogenicity and safety of a pentavalent vaccine Gobik (DPT-IPV-Haemophilus influenzae type b [Hib]) in healthy Japanese infants aged ≥ 2 and < 43 months using a concomitant vaccination with ActHIB® (Hib) and Tetrabik (DPT-IPV) as a comparator. METHODS: This study was conducted as a phase 3, multicenter, active controlled, assessor-blinded, randomized, parallel-group study. Participants received a total of 4 subcutaneous doses (3 primary immunization doses and a booster dose) of either the experimental drug (DPT-IPV-Hib) or the active comparator (Hib + DPT-IPV). The primary endpoints were the anti-PRP antibody prevalence rate with ≥ 1 µg/mL, and the antibody prevalence rates against pertussis, diphtheria toxin, tetanus toxin, and attenuated poliovirus after the primary immunization. RESULTS: In 267 randomized participants (133 in the DPT-IPV-Hib group and 134 in the Hib + DPT-IPV group), the antibody prevalence rates after the primary immunization in both groups were 100.0 % and 88.7 % for anti-PRP antibody with ≥ 1 µg/mL, 99.2 % and 98.5 % against diphtheria toxin, and 100.0 % and 99.2 % against tetanus toxin, respectively. The antibody prevalence rates against pertussis and attenuated poliovirus were 100.0 % in both groups. The non-inferiority of the DPT-IPV-Hib group to the Hib + DPT-IPV group was verified for all measured antibodies. In both groups, all the GMTs of antibodies after the primary immunization were higher than those before the first dose, and those after the booster dose were higher than those after the primary immunization. No safety issues were identified. CONCLUSION: A single-agent Gobik, the first DPT-IPV-Hib pentavalent vaccine approved in Japan, was confirmed to simultaneously provide primary and booster immunizations against Hib infection, pertussis, diphtheria, tetanus, and poliomyelitis and to have a preventive effect and safety comparable to concomitant vaccination with Hib (ActHIB®) and DPT-IPV quadrivalent vaccine (Tetrabik).

Collaborative study for the establishment of Ph. Eur. Biological Reference Preparation for Human tetanus immunoglobulin batch 2.

This publication describes the outcome of a project to develop a replacement European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human tetanus immunoglobulin (TIg) as well as for the World Health Organization (WHO) International Standard (IS) for Tetanus Immunoglobulin, Human. Bulk TIg was kindly provided by a European manufacturer and was used to prepare the candidate standard. The candidate standard was freeze-dried and calibrated in an international collaborative study jointly co-ordinated by the Medicines & Healthcare products Regulatory Agency (MHRA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe). The results of this study show that there was good agreement between laboratories for the potency estimates obtained for the candidate standard relative to the current WHO IS/Ph. Eur. BRP. The study also demonstrated that the candidate standard is suitable for use in Ph. Eur. assays for potency testing of TIg products and there was good agreement in the potency estimates obtained using the different assay methods included in the study. Accelerated degradation studies performed at the MHRA over a period of 4 years suggest that the freeze-dried candidate standard will be very stable. The candidate standard was established as Ph. Eur. BRP for Human tetanus immunoglobulin, batch 2 with an assigned potency of 45 IU/ampoule. The same preparation was also adopted by the WHO Expert Committee on Biological Standardization (ECBS) to serve as the WHO 2nd IS for Tetanus Immunoglobulin, Human (13/240).

Impact of steroids on the immune profiles of children with asthma living in the inner-city.

Background: Inner-city asthma is associated with high morbidity and systemic steroid use. Chronic steroid use impacts immune function; however, there is a lack of data with regard to the extent of immunosuppression in patients with asthma and who are receiving frequent systemic steroids. Objective: To identify the impact of frequent systemic steroid bursts on the immune function of children with asthma who live in the inner city. Methods: Children ages 3-18 years with asthma were divided into study (≥2 systemic steroid bursts/year) and control groups (0-1 systemic steroid bursts/year). Lymphocyte subsets; mitogen proliferation assay; total immunoglobulin G (IgG) value, and pneumococcal and diphtheria/tetanus IgG values were evaluated. Results: Ninety-one participants were enrolled (study group [n = 42] and control group [n = 49]). There was no difference in adequate pneumococcal IgG value, diphtheria/tetanus IgG value, mitogen proliferation assays, lymphocyte subsets, and IgG values between the two groups. Children who received ≥2 steroid bursts/year had a significantly lower median pneumococcal IgG serotype 7F value. Most of the immune laboratory results were normal except for the pneumococcal IgG value. Most of the participants (n/N = 72/91 [79%]) had an inadequate pneumococcal IgG level (<7/14 serotypes ≥1.3 µg/mL). The participants with inadequate pneumococcal IgG level and who received a pneumococcal polysaccharide vaccine 23 (PPSV23) boost had a robust response. There was no significant difference in infection, steroid exposure, asthma severity, or morbidities between those with adequate versus inadequate pneumococcal IgG values. Conclusion: Children with asthma who live in the inner city and receive ≥2 steroid bursts/year do not have a significantly different immune profile from those who receive ≤1 steroid bursts/year do not have a significantly different immune profile from those who do not. Although appropriately vaccinated, most participants had an inadequate pneumococcal IgG level, regardless of steroid exposure and asthma severity. These children may benefit from PPSV23.

Antiviral responses induced by Tdap-IPV vaccination are associated with persistent humoral immunity to Bordetella pertussis.

Many countries continue to experience pertussis epidemics despite widespread vaccination. Waning protection after booster vaccination has highlighted the need for a better understanding of the immunological factors that promote durable protection. Here we apply systems vaccinology to investigate antibody responses in adolescents in the Netherlands (N = 14; NL) and the United Kingdom (N = 12; UK) receiving a tetanus-diphtheria-acellular pertussis-inactivated poliovirus (Tdap-IPV) vaccine. We report that early antiviral and interferon gene expression signatures in blood correlate to persistence of pertussis-specific antibody responses. Single-cell analyses of the innate response identified monocytes and myeloid dendritic cells (MoDC) as principal responders that upregulate antiviral gene expression and type-I interferon cytokine production. With public data, we show that Tdap vaccination stimulates significantly lower antiviral/type-I interferon responses than Tdap-IPV, suggesting that IPV may promote antiviral gene expression. Subsequent in vitro stimulation experiments demonstrate TLR-dependent, IPV-specific activation of the pro-inflammatory p38 MAP kinase pathway in MoDCs. Together, our data provide insights into the molecular host response to pertussis booster vaccination and demonstrate that IPV enhances innate immune activity associated with persistent, pertussis-specific antibody responses.

Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups.

Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague-Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon.

Seroprevalence of tetanus and pertussis antibodies among health care workers in Wuhu, China.

This study aimed to elucidate the seroprevalence of antibodies to tetanus and pertussis among Chinese health care workers. Blood specimens from health care workers were collected during the 2021 annual medical examination at the First People's Hospital of Wuhu. Commercial ELISA kits were employed to quantify serum IgG antibodies against tetanus toxin (anti-TT IgG) and both IgG and IgA antibodies against pertussis toxin (anti-PT IgG, anti-PT IgA). A concentration of anti-TT IgG exceeding 0.1 IU/ml was deemed seroprotective against tetanus, while concentrations of anti-PT IgG ≥ 50 IU/ml or anti-PT IgA ≥ 15 IU/ml were indicative of a prior pertussis infection. The overall seroprotective rate for anti-TT IgG stood at 10.43% (92/882), with the highest seroprotective rate (13.91%) in the 20-29 age group, followed by the 30-39 age group (10.57%), 40-49 age group (5.80%), and 50-59 age group (5.63%). Eighteen (2.04%) of the studied subjects were positive to anti-PT IgG, and the positive rate in 20-39 age group and 40-59 age group was 1.19% (8/673) and 4.78% (10/209), respectively. Thirty (3.40%) subjects displayed anti-PT IgG levels ≥100 IU/ml and/or anti-PT IgA ≥ 15 IU/ml, suggesting a recent pertussis infection within the preceding year. Over half (503/882, 57.03%) had undetectable anti-PT IgG antibodies. The majority of health care workers in China appear susceptible to tetanus and pertussis, and a significant subset has experienced pertussis infection. The implementation of booster vaccinations against these diseases for Chinese health care workers is recommended.

Protective doses of tetanus toxoid immunization and its associated factors among mothers in southern Ethiopia.

The World Health Organization recommends tetanus toxoid immunization before or during pregnancy for all women of childbearing age. The goal is to reduce maternal and neonatal mortality due to tetanus. According to the 2016 Ethiopia Demographic and Health Survey (EDHS) report, more than half (51%) of women did not receive protective doses of tetanus immunization. To the best of our knowledge, this study uniquely tried to assess the level of protective doses of tetanus toxoid immunization in southern Ethiopia. A community-based cross-sectional study was conducted among 580 randomly selected participants. Variable with p-value of less than .25 in the bivariate analysis were included in the multivariable logistic regression analysis. Finally, statistical significance was declared at a p-value of less than .05. The proportion of protective doses of tetanus toxoid immunization uptake in the area was found to be 41.9% (95% CI: 38-46%). Being enrolled in formal education [AOR = 6.55, 95% CI: 3.23-9.01], having at least two postnatal care visits [AOR = 3.82; 95% CI: 1.78-6.40], having at least four antenatal care visits [AOR = 2.56; 95% CI: 1.41-4.34], and being visited by Health Extension Workers [AOR = 2.66; 95% CI: 1.42-4.01] were found to be factors enhancing the uptake of protective doses of tetanus toxoid immunization. Generally, the uptake or prevalence of the protective doses of tetanus toxoid immunization in the area was lower than the World Health Organization's target. Therefore, all responsible bodies, including healthcare providers, need to strengthen counseling mothers to enhance the uptake of tetanus toxoid immunization.

Immunogenicity at delivery after Tdap vaccination in successive pregnancies.

Background: Tetanus, diphtheria, acellular pertussis (Tdap) vaccination is recommended to be administered in every pregnancy. Although the safety of this strategy has been confirmed, the immunogenicity of Tdap vaccination in two successive pregnancies has not yet been described. This study investigated Tdap-specific immunity levels and transplacental transfer in two successive pregnancies after repeated Tdap-vaccination. Methods: Women enrolled in prior studies on Tdap vaccination during pregnancy were invited to participate in a follow-up study if they became pregnant again. Women who received a Tdap vaccine in both pregnancies were considered for this analysis. Tdap-specific total IgG and IgG subclasses were measured with a multiplex immunoassay. Results: In total, 27 participants with a mean interval between deliveries of 2.4 years were included in the analysis. In maternal serum, Tdap-specific total IgG levels were comparable at both deliveries whereas in cord serum, all Tdap-specific total IgG antibody levels were reduced at the second compared to the first delivery. This was largely reflected in the IgG1 levels in maternal and cord serum. Transplacental transfer ratios of total IgG and IgG1 were also mostly reduced in the second compared to the first pregnancy. Conclusion: This study reports for the first time Tdap-specific total IgG and IgG subclass levels and transfer ratios after repeated Tdap vaccination in successive pregnancies. We found reduced transfer of most Tdap-specific IgG and IgG1 antibodies in the successive pregnancy. As pertussis-specific antibodies wane quickly, Tdap vaccination in each pregnancy remains beneficial. However, more research is needed to understand the impact of closely spaced booster doses during pregnancy on early infant protection against pertussis.

Quantitative analysis of pertussis, tetanus, and diphtheria antibodies in sera and breast milk from Tdap vaccinated women using a qualified multiplex assay.

Pertussis (whooping cough) is a reemergent, highly contagious respiratory infection of public health concern. Infants prior to initiation of their primary vaccination series are the most vulnerable to severe infection, and even death. Vaccination during pregnancy is an efficacious means of reducing infection in infants. This approach relies on boosting maternal immunity and passive transfer of antibodies to the infant via placenta and breast milk. Similarly, maternal vaccination post-partum can enhance maternal-infant immunity. To support the analysis of pertussis immunity in the context of maternal-infant immunization, we developed a high throughput multiplex assay for simultaneous quantification of serum IgG antibodies against pertussis vaccine antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM2/3), and against tetanus (TT) and diphtheria toxoids (DT), using the Meso Scale Discovery (MSD) platform. The assay was qualified, and specificity, sensitivity, accuracy, precision, linearity, and robustness were demonstrated. The assay was subsequently adapted for quantification of IgG and IgA in breast milk. Applied to a serological survey of pregnant women living in the United States and sub-Saharan Africa, this method revealed differences in magnitude and breadth of antibody profile, consistent with history of vaccination. A longitudinal analysis of Tdap responses in women vaccinated post-partum demonstrated a rapid increase in serum IgG that remained elevated for up to 24 months. Likewise, high levels of vaccine-specific IgA and IgG antibodies were present in breast milk, although they exhibited faster decay. This multiplex MSD assay is a reliable and practical tool for quantification of pertussis, tetanus, and diphtheria antibodies in serum and breast milk in serosurveys or vaccine studies. IMPORTANCE: Pertussis (whooping cough) has reemerged in recent years. Vaccination during pregnancy is an effective approach to prevent illness during the first months of life. We developed a multiplex assay for quantification of pertussis, tetanus, and diphtheria serum antibodies using the Meso Scale Discovery (MSD) platform; the method was qualified, and specificity, precision, accuracy, linearity, and limits of quantification were defined. It was also adapted for quantification of antibodies in breast milk. We successfully determined serostatus in women from different regions and with different vaccination histories, as well as responses to Tdap in blood and breast milk post-partum. This is the first description of a multiplex assay for the quantification of pertussis, tetanus, and diphtheria antibodies in breast milk.

Management and outcome of adult generalized tetanus in a Chinese tertiary hospital.

Background: Tetanus is a rare surgical infectious disease with a high reported relevant mortality. It still remains a serious problem in public health, particularly in low-income and middle-income countries. The purpose of this study was to investigate the management and prognosis of adult generalized tetanus in our hospital. Methods: A total of 20 adult generalized tetanus patients were recruited in this retrospective observational study. Patients were retrieved from the hospital data base via discharge diagnosis. Patients were divided into two groups (Severe or Non-severe tetanus group) based on the severity of tetanus by using the Ablett classification. The differences between the two groups were compared. Results: The study included 11 males (55%) and 9 females (45%). All tetanus patients recovered. The median age was 53.5 years [IQR: 19-78]. There were 1 mild (Grade 1) case (5%),5 moderate (Grade 2) cases (25%), 2 severe (Grade 3) cases (10%), and 12 very severe (Grade 4) cases (60%). Nineteen patients (95%) did not have tetanus immunization before. The majority of patients were farmers (60%), and came from rural areas (60%). Thirteen (65%) patients had a history of puncture injury. The rate of wound debridement after admission was 60% overall. Thirteen (65%) patients required mechanical ventilation for a median of 21 [IQR:12-41] days. Autonomic instability occurred in 13 (65%) patients. Pulmonary infections occurred in 12 (60%) patients. Median duration of hospital stay was 29.5 [IQR:12-68] days. More patients in the Severe group needed ICU admission, wound debridement, mechanical ventilation and heavy sedation combined with muscle relaxants (p < 0.05). The hospital stay was significantly longer in patients in the Severe group (p < 0.05). Conclusion: After effective treatment, all adult patients with generalized tetanus in this study were cured and discharged. Severe tetanus requires early ICU treatment, wound debridement and effective treatment of autonomic instability.