Single and two-dose typhoid conjugate vaccine safety and immunogenicity in HIV-exposed uninfected and HIV-unexposed uninfected Malawian children.

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Immunogenicity and Safety of a Quadrivalent Meningococcal Tetanus Toxoid-Conjugate Vaccine (MenACYW-TT) in Meningococcal Vaccine-Naïve Participants across a Broad Age Range (2-55 Years) in Japan: a Phase III Randomized Study.

MenACYW-TT is a quadrivalent meningococcal tetanus toxoid-conjugate vaccine designed to prevent invasive meningococcal disease. The primary objective of this study was to demonstrate non-inferiority of the vaccine seroresponse to a single dose of MenACYW-TT compared with MCV4-DT, a licensed meningococcal quadrivalent diphtheria-conjugate vaccine. This Phase III double-blind, multicenter trial was conducted in meningococcal vaccine-naïve individuals aged 2-55 years in Japan (NCT04368429; jRCT2080225192). Participants were randomized 1:1 to receive either MenACYW-TT (n = 180) or MCV4-DT (n = 180). Functional antibodies against meningococcal serogroups A, C, W, and Y were measured using a serum bactericidal antibody assay with human complement (hSBA) at baseline (D0) and 30 days after vaccination (D30). Seroresponse was defined as a post-vaccination titer ≥1:16 in participants with a baseline titer <1:8; or a ≥4-fold increase in titer in participants with a baseline titer ≥1:8. Safety data were collected for 30 days. Non-inferiority of the seroresponse to MenACYW-TT vs. MCV4-DT was demonstrated on D30 for each serogroup tested (A: 85.6% vs. 65.4%; C: 96.6% vs. 62.6%; W: 87.4% vs. 49.2%; Y: 97.7% vs. 63.5%). MenACYW-TT was well tolerated with no safety concerns identified. A single dose of MenACYW-TT was well tolerated, with a non-inferior seroresponse compared with MCV4-DT. MenACYW-TT could thus be used as an alternative vaccine in meningococcal vaccine-naïve individuals.

Safety, immunogenicity and non-interference of concomitant Typhoid Vi capsular polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV®) and measles or measles-mumps-rubella vaccines in 8-9 months-old Indian children.

We evaluated safety, reactogenicity, and immunogenicity when the WHO-prequalified single-dose Typhoid Vi-polysaccharide conjugate vaccine, Typbar-TCV®, was administered concomitantly with measles (MV) or measles-mumps-rubella (MMR) vaccines in 8- or 9-month-old children. We enrolled 493 children who were randomized 2:1:1:1 to four groups to receive either TCV (0.5 mL intramuscularly) and MV (0.5 ml subcutaneously) concomitantly at 9 months of age (Group 1) with two subgroups given TCV booster 28 days (Group 1A) or 180 days (Group 1B) later, or MV on Day 0 and TCV on Day 28 (Group 2); or TCV at 8 months of age and MV 28 days later (Group 3), or MV only at 9 months of age (Group 4). All children received MMR at 15 months of age. We observed no statistically significant differences between group rates of solicited or unsolicited adverse events assessed throughout the study. Seroconversion rates for measles, mumps, and rubella antibodies were unaffected by concomitant administration with TCV, being similar in Groups 1, 2, and 3 and comparable to Group 4 (Control). IgG anti-Vi antibody titers were similar in all groups after primary Typbar-TCV® vaccination and were not increased by a second dose 28 days later. A small response to a booster dose of Typbar-TCV® given at 180 days did not achieve the high titers observed after the first dose, suggesting that booster vaccination may be more effective after a longer interval than 6 months. Typbar-TCV® can be safely co-administered with measles and MMR vaccines in children aged ≥9 months.Clinical trial registration number: CTRI/2014/04/004532.

Clinical trial and postmarketing safety experience with MenACWY-TT, a meningococcal group A, C, W, and Y tetanus conjugate vaccine.

BACKGROUND: The meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®; Pfizer Ltd, Sandwich, Kent, UK) is licensed in more than 80 countries worldwide for the prevention of meningococcal disease caused by serogroups A, C, W, and Y in individuals throughout their lifespans. This report summarizes safety data from the MenACWY-TT clinical development program and postmarketing experience. METHODS: Within the clinical study program, reactogenicity data were based on 3 primary studies, including a large pooled analysis across multiple age groups, and long-term safety data were derived from 3 studies evaluating long-term antibody persistence. Postmarketing safety data through April 19, 2021, were collected and analyzed in connection with the MenACWY-TT Periodic Safety Update Report. RESULTS: Approximately 32 million doses of MenACWY-TT have been administered worldwide, with more than 21,530 additional individuals receiving MenACWY-TT as part of clinical trials. The safety profile of MenACWY-TT was consistent between the clinical study program and the postmarketing experience, as well as with other licensed meningococcal vaccines. The most commonly observed adverse events (AEs) were pyrexia/fever, headache, injection site pain/reactions, nausea/vomiting, and fatigue; serious AEs were rare relative to the number of doses administered. Several cases of serogroup replacement/lack of efficacy were observed in the 1-year postmarketing period but did not appear to be related to MenACWY-TT use. CONCLUSION: Extensive data derived from clinical trials and postmarketing experience indicate a consistently favorable safety profile for MenACWY-TT across a wide range of age groups.

Genetically detoxified tetanus toxin as a vaccine and conjugate carrier protein.

Tetanus toxoid (TTxd), developed over 100 years ago, is a clinically effective, legacy vaccine against tetanus. Due to the extreme potency of native tetanus toxin, manufacturing and regulatory efforts often focus on TTxd production, standardization, and safety, rather than product modernization. Recently, a genetically detoxified, full-length tetanus toxin protein (8MTT) was reported as a tetanus vaccine alternative to TTxd (Przedpelski et al. mBio, 2020). Here we describe the production of 8MTT in Gor/MetTM E. coli, a strain engineered to have an oxidative cytoplasm, allowing for the expression of soluble, disulfide-bonded proteins. The strain was also designed to efficiently cleave N-terminal methionine, the obligatory start amino acid for E. coli expressed proteins. 8MTT was purified as a soluble protein from the cytoplasm in a two-column protocol to > 99 % purity, yielding 0.5 g of purified 8MTT/liter of fermentation broth with low endotoxin contamination, and antigenic purity of 3500 Lf/mg protein nitrogen. Mouse immunizations showed 8MTT to be an immunogenic vaccine and effective as a carrier protein for peptide and polysaccharide conjugates. These studies validate 8MTT as commercially viable and, unlike the heterogenous tetanus toxoid, a uniform carrier protein for conjugate vaccines. The development of a recombinant, genetically detoxified toxin produced in E. coli aligns the tetanus vaccine with modern manufacturing, regulatory, standardization, and safety requirements.

A multi-centre, post-marketing surveillance study of Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®) in India.

A typhoid Vi capsular-polysaccharide tetanus toxoid conjugate vaccine (Typbar-TCV®) was recommended by the World Health Organization for use in children >6 months of age. The present post-marketing surveillance study was intended to assess the clinical safety of approximately 11 million doses of TCV sold till 2019 in a diverse age range Indian population. Both active and passive post-marketing surveillance studies were conducted at multiple centers. Active surveillance was performed in two periods, Period-I: February to October 2016, Period-II: April 2017 to October 2018. In Period-II, the Brighton Collaboration Criteria adverse event case definitions were used. Passive surveillance was performed from February 2016 to December 2019 through voluntary reporting by pediatricians across India. During the active surveillance, 1147 adverse events were reported among 4,991 (23.0%) subjects in Period-I, and 596 adverse events among 3898 (21.3%) subjects in Period-II. The most frequent adverse events were fever (9.2% and 12.02%in Periods I and II, respectively), pain at the injection site (8.3% and 7.33%), and swelling (4.0% and 1.93%). No serious adverse events (SAEs) were reported during either Period. Passive surveillance revealed 235 adverse events, including 25 SAEs requiring hospitalization, of which two were due to typhoid fever. All the events mentioned above occurred within one week of vaccination, and all the subjects have recovered from AEs with medications. All reported adverse events resolved with no clinical sequelae. Observations in this study are consistent with the pre-licensure studies with no additional safety signals detected, confirming that Typbar-TCV® is safe.Abbreviations: AE: Adverse event; LMIC: low- and middle-income countries; PMS: Post-marketing surveillance; SAE: Serious adverse event; TCV: Vi-polysaccharide tetanus -toxoid conjugate vaccine (Typbar-TCV®).

Perinatal mortality and its association with antenatal care visit, maternal tetanus toxoid immunization and partograph utilization in Ethiopia: a meta-analysis.

Despite remarkable progress in the reduction of under-five mortality; perinatal mortality is the major public health problem in Africa. In Ethiopia, the study findings on perinatal mortality and its predictors were inconsistent. Therefore, this systematic review and meta-analysis estimated the pooled perinatal mortality, and its association with antenatal care visit, maternal tetanus toxoid immunization, and partograph monitoring. International databases like PubMed, SCOPUS, Google Scholar and Science Direct were systematically searched. I squared statistics was used to determine the levels of heterogeneity across studies and the pooled estimate was computed using a random-effect model. The meta-analysis showed that a pooled prevalence of perinatal mortality in Ethiopia was 6.00% (95% CI 5.00%, 7.00%). The highest proportion of perinatal mortality was a stillbirth, 5.00% (95% CI 4.00%, 7.00%). Women who had antenatal care visit [OR = 0.20 (95% CI 0.12, 0.34)], maternal tetanus toxoid immunization [OR = 0.43 (95% CI 0.24, 0.77)] and partograph monitoring [POR = 0.22 (95% CI 0.06, 0.76)] reduced the risk of perinatal mortality. Whereas, previous history of perinatal mortality [POR = 7.95 (95% CI 5.59, 11.30)] and abortion history (POR = 2.02 (95% CI 1.18, 3.46)) significantly increased the risk of perinatal mortality. Therefore, antenatal care visit, maternal tetanus toxoid vaccination uptake, and partograph utilization should be an area of improvements to reduce perinatal mortality.

Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

Tetanus is a fatal but vaccine-preventable disease. The currently available tetanus vaccines are tetanus toxoid (TT)-based. Although these vaccines are generally effective, challenges in vaccine development and access remain. A randomized, double-blind, dose escalation, placebo- and positive-controlled, phase 1/2 trial (ChiCTR1800015865) is performed to evaluate the safety and immunogenicity of an alternative recombinant tetanus vaccine based on the Hc domain of tetanus neurotoxin (TeNT-Hc) in healthy adult volunteers. The primary outcome is the safety profile of the recombinant tetanus vaccine, and immunogenicity is the secondary outcome. 150 eligible participants were enrolled and randomly assigned to receive one of the three doses of recombinant tetanus vaccine (TeNT-Hc 10/20/30 µg), TT vaccine, or placebo. The recombinant tetanus vaccine shows a good safety profile. The frequency of any solicited and unsolicited adverse events after each vaccination does not differ across the vaccine and placebo recipients. No serious treatment-related adverse events occur. The recombinant tetanus vaccine shows strong immune responses (seroconversion rates, geometric mean titer, and antigen-specific CD4+/CD8+ T-cell responses), which are roughly comparable to those of the TT vaccine. In conclusion, the findings from this study support that recombinant tetanus vaccine is safe and immunogenic; thereby, it represents a novel vaccine candidate against tetanus.

Clinical Decision Support Reduces Unnecessary Tetanus Vaccinations in the Emergency Department.

STUDY OBJECTIVE: Tetanus is the most common vaccination given in the emergency department; yet, administrations of tetanus vaccine boosters in the ED may not comply with the US Centers for Disease Control and Prevention's recommended vaccination schedule. We implemented a clinical decision support alert in the electronic health record that warned providers when ordering a tetanus vaccine if a prior one had been given within 10 years and studied its efficacy to reduce potentially unnecessary vaccines in the ED. METHODS: This was a retrospective, quasi-experimental, 1-group, pretest-posttest study in 3 hospital EDs in Boston, MA. We studied adult patients for whom tetanus vaccines were ordered despite a history of vaccination within the prior 10 years. We compared the number of potentially unnecessary tetanus vaccine administrations in a baseline phase (when the clinical decision support alert was not visible) versus an intervention phase. RESULTS: Of eligible patients, 22.1% (95% confidence interval [CI] 21.8% to 22.4%) had prior tetanus vaccines within 5 years, 12.8% (95% CI 12.5% to 13.0%) within 5 to 10 years, 3.8% (95% CI 3.6% to 3.9%) more than 10 years ago, and 61.3% (95% CI 60.9% to 61.7%) had no prior tetanus vaccination documentation. Of 60,983 encounters, 337 met the inclusion criteria. A tetanus vaccination was administered in 91% (95% CI 87% to 96%) of encounters in the baseline phase, compared to 55% (95% CI 47% to 62%) during the intervention. The absolute risk reduction was 36.7% (95% CI 28.0% to 45.4%), and the number of encounters needed to alert to avoid 1 potentially unnecessary tetanus vaccine (number needed to treat) was 2.7 (95% CI 2.2% to 3.6%). For patients with tetanus vaccines within the prior 5 years, the absolute risk reduction was 47.9% (95% CI 35.5 % to 60.3%) and the number needed to treat was 2.1 (95% CI 1.7% to 2.8%). CONCLUSION: A clinical decision support alert that warns ED clinicians that a patient may have an up-to-date tetanus vaccination status reduces potentially unnecessary vaccinations.