Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study.

Background: While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. Methods: In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. Findings: 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Interpretation: Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. Funding: This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

Intravenous Immunoglobulin and Dermatomyositis-Associated Venous Thromboembolism.

This cohort study investigated the association between treatment of dermatomyositis with intravenous immunoglobulin and thromboembolic events.

Assessing the generation of tissue resident memory T cells by vaccines.

Vaccines have been a hugely successful public health intervention, virtually eliminating many once common diseases of childhood. However, they have had less success in controlling endemic pathogens including Mycobacterium tuberculosis, herpesviruses and HIV. A focus on vaccine-mediated generation of neutralizing antibodies, which has been a successful approach for some pathogens, has been complicated by the emergence of escape variants, which has been seen for pathogens such as influenza viruses and SARS-CoV-2, as well as for HIV-1. We discuss how vaccination strategies aimed at generating a broad and robust T cell response may offer superior protection against pathogens, particularly those that have been observed to mutate rapidly. In particular, we consider here how a focus on generating resident memory T cells may be uniquely effective for providing immunity to pathogens that typically infect (or become reactivated in) the skin, respiratory mucosa or other barrier tissues.

Safety and Immunogenicity of Influenza A/H5N8 Virus Vaccine in Healthy Adults: Durability and Cross-reactivity of Antibody Responses.

BACKGROUND: Influenza A/H5N8 viruses infect poultry and wild birds in many countries. In 2021, the first human A/H5N8 cases were reported. METHODS: We conducted a phase I, cohort-randomized, double-blind, controlled trial of inactivated influenza A/H5N8 vaccine (clade 2.3.4.4c) administered with or without adjuvant. Cohort 1 subjects received either two doses of AS03-adjuvanted vaccine containing 3.75 µg or 15 µg hemagglutinin (HA); two doses of 15 µg HA unadjuvanted vaccine; or one dose of AS03-adjuvanted vaccine (3.75 µg or 15 µg HA), followed by one dose of non-adjuvanted vaccine (same HA content). Cohort 2 subjects received two doses of MF59-adjuvanted vaccine containing 3.75 µg or 15 µg HA, or 15 µg HA of non-adjuvanted vaccine. Subjects were followed for 13 months for safety and immunogenicity. RESULTS: We enrolled 386 adult subjects in good health. Solicited adverse events were generally mild and more common among subjects who received adjuvanted vaccines. Antibody responses (hemagglutination inhibition or microneutralization assays) were highest in the two-dose AS03 group, followed by the one-dose AS03 group, the MF59 groups, and the non-adjuvanted groups. Antibody levels returned to baseline 12 months after the second vaccination in all groups except the 15 µg AS03-adjuvanted group. Cross-reactive antibodies to clade 2.3.4.4b strains isolated from recent human cases were demonstrated in a subset of both 15 µg adjuvanted groups. CONCLUSIONS: Two doses of influenza A/H5N8 vaccine were well-tolerated. Immunogenicity improved with receipt of two doses of adjuvanted vaccine and higher antigen content. (Funded by the National Institute of Allergy and Infectious Diseases.

Supravenous Repigmentation of Hair Shafts in a Patient with Regrowing Alopecia Totalis: A Case Report and Hypothesis.

Introduction: Alopecia areata (AA) is a type of nonscarring alopecia that has autoimmune etiology, in which the hair follicle, usually an immune-privileged site, becomes the target of attack. Alopecia totalis (AT) is a subset of AA in which patients completely lose hair on the scalp. Initial hair regrowth is often fine and without pigment. We present a case of AT in which pigmented hair grew only overlying superficial veins, a finding which has not been previously reported. Case Presentation: An adult female with brown hair presented with AA that progressed to AT despite the use of triamcinolone ointment and topical 2% tofacitinib ointment. She was treated with nightly augmented betamethasone dipropionate 0.05% ointment under occlusion. Two months later, she noticed diffuse regrowth of thin hair on her scalp, most of which was depigmented. However, linear bands of darkly pigmented hairs were noted overlying superficial scalp veins. Discussion/Conclusion: Loss of pigmentation and subsequent repigmentation of the hair shaft in regrowing AA is not entirely understood. Initial hair regrowth in AA tends to be fine and depigmented, although the hair will usually regain normal texture and color. Pigmentation following a vein suggests that local temperature may play a role, possibly augmented by corticosteroid induced reduced expression of inflammatory cytokines and endothelial release of the vasoconstrictor hormone endothelin, which stimulates melanogenesis.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: A randomized controlled phase 2 trial.

OBJECTIVES: In 2017, the World Health Organisation (WHO) pre-qualified a single-dose typhoid conjugate vaccine (TCV) and identified TCV co-administration studies as a research priority. Accordingly, we tested co-administration of Typbar TCV® (Bharat Biotech International) with measles-rubella (MR) and yellow fever (YF) vaccines. METHODS: We conducted a randomized, double-blind, and controlled, phase 2 trial in Ouagadougou, Burkina Faso. Healthy children aged 9-11 months were randomized 1:1 to receive TCV (Group 1) or control vaccine (inactivated polio vaccine (IPV), Group 2). Vaccines were administered intramuscularly with routine MR and YF vaccines. Safety was assessed by (1) local and systemic reactions on days 0, 3, and 7; (2) unsolicited adverse events within 28 days; and (3) serious adverse events (SAEs) within six months after immunization. RESULTS: We enrolled, randomized, and vaccinated 100 eligible children (49 Group 1 and 51 Group 2). Safety outcomes occurred with similar frequency in both groups: local/solicited reactions (Group 1: 1/49, Group 2: 3/50), systemic/solicited reactions (Group 1: 4/49, Group 2: 9/50), unsolicited adverse events (Group 1: 26/49, Group 2: 33/51), and SAEs (Group 1: 2/49, Group 2: 3/51). TCV conferred robust immunogenicity without interference with MR or YF vaccines. CONCLUSION: TCV can be safely co-administered with MR and YF vaccines to children at the 9-month vaccination visit.

Safety and immunogenicity of co-administration of meningococcal type A and measles-rubella vaccines with typhoid conjugate vaccine in children aged 15-23 months in Burkina Faso.

OBJECTIVES: The World Health Organization pre-qualified single-dose typhoid conjugate vaccine (TCV) and requested data on co-administration with routine vaccines. The co-administration of Typbar TCV (Bharat Biotech International) with routine group A meningococcal conjugate vaccine (MCV-A) and measles-rubella (MR) vaccine was tested. METHODS: This was a double-blind, randomized controlled trial performed in Ouagadougou, Burkina Faso. Children were recruited at the 15-month vaccination visit and were assigned randomly (1:1:1) to three groups. Group 1 children received TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; group 2 children received TCV and MCV-A; group 3 children received MCV-A and control vaccine. Routine MR vaccine was administered to all participants. Safety was assessed at 0, 3, and 7 days after immunization, and unsolicited adverse events and serious adverse events were assessed for 28 days and 6 months after immunization, respectively. RESULTS: A total of 150 children were recruited and vaccinated. Solicited symptoms were infrequent and similar for TCV and control recipients, as were adverse events (group 1, 61.2%; group 2, 64.0%; group 3, 68.6%) and serious adverse events (group 1, 2.0%; group 2, 8.0%; group 3, 5.9%). TCV generated robust immunity without interference with MCV-A vaccine. CONCLUSIONS: TCV can be safely co-administered at 15 months with MCV-A without interference. This novel study on the co-administration of TCV with MCV-A provides data to support large-scale uptake in sub-Saharan Africa.

Typhoid Vaccine Acceleration Consortium Malawi: A Phase III, Randomized, Double-blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine Among Children in Blantyre, Malawi.

BACKGROUND: Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5-15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi. METHODS: In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018. RESULTS: All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture-confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events. CONCLUSIONS: The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world's poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting. CLINICAL TRIALS REGISTRATION: NCT03299426.

A Phase II, Randomized, Double-blind, Controlled Safety and Immunogenicity Trial of Typhoid Conjugate Vaccine in Children Under 2 Years of Age in Ouagadougou, Burkina Faso: A Methods Paper.

The recent Typhoid Fever Surveillance in Africa Program demonstrated an overall adjusted incidence of typhoid fever 2-3 times higher than previous estimates in Africa. Recently, a single-dose typhoid conjugate vaccine that allows infants as young as 6 months old to be vaccinated was prequalified by the World Health Organization (WHO). This Vi-based conjugate vaccine demonstrated robust immunogenicity after 1 dose in infants and children 6 through 23 months of age in India with no safety signal, and is currently being tested for the first time on the African continent in Malawi. The WHO Strategic Advisory Group of Experts recommends studies to evaluate co-administering Vi-typhoid conjugate vaccine (Vi-TCV) with routine childhood vaccines in typhoid-endemic countries. The Burkina Faso immunization schedule includes yellow fever vaccine (YFV) at 9 months and meningococcal A conjugate vaccine (MCV-A) at 15 months, in addition to measles-rubella vaccine at both 9 and 15 months. Co-administration testing of Vi-TCV with these routine vaccinations will provide the data needed to support large-scale uptake of Vi-TCV in sub-Saharan Africa. A randomized, controlled, Phase II trial of Vi-TCV co-administration with the vaccinations routinely given at 9 and 15 months of age is planned in Burkina Faso. The overall aim is to assess the safety and immunogenicity of Vi-TCV when co-administered with YFV at 9 months of age and with MCV-A at 15 months of age. A total of 250 participants (100 infants aged 9-11 months and 150 children aged 15-23 months) will be enrolled. Clinical Trials Registration. NCT03614533.

Influenza Among Young Children in Bangladesh: Clinical Characteristics and Outcomes From a Randomized Clinical Trial.

BACKGROUND: Influenza causes substantial morbidity in children worldwide, although influenza vaccine is seldom used in low-resource settings. More information on the clinical presentation of influenza and the efficacy of vaccine is needed to inform policy. METHODS: In 2013 we conducted a randomized, placebo-controlled clinical trial of live attenuated influenza vaccine (LAIV) in children aged 24-59 months in Bangladesh (N = 1761). If participants met prespecified specimen collection criteria, we collected nasopharyngeal washes for testing by singleplex reverse-transcription polymerase chain reaction (RT-PCR) for laboratory-confirmed influenza virus infection (LCI). A panel of RT-PCR assays was used to detect noninfluenza respiratory viruses. Primary efficacy results have been reported. In this analysis of prespecified and post hoc objectives from the trial, we compared signs and symptoms between LCI and non-LCI cases and estimated the efficacy of LAIV against moderate-to-severe LCI and other prespecified non-LCI clinical outcomes including all-cause pneumonia and acute otitis media. RESULTS: The most common signs and symptoms of LCI were fever, cough, and runny nose. The combination of subjective fever and cough had a 63% sensitivity for LCI. The combination of measured fever, cough, and runny nose was most specific (90%) but had low sensitivity (32%) for LCI. The efficacy of LAIV against vaccine-strain moderate-to-severe LCI was 56.7% (95% confidence interval, 9.5%-79.2%). No statistically significant vaccine efficacy was found against the non-laboratory-confirmed clinical outcomes. CONCLUSIONS: It was not possible to distinguish LCI from noninfluenza viral infections on clinical evaluations alone in this population of Bangladeshi children. LAIV was efficacious against moderate-to-severe LCI. CLINICAL TRIALS REGISTRATION: NCT01797029.

Influenza: A Global Perspective.

Influenza is a common respiratory illness in children and accounts for substantial morbidity and mortality on an annual basis. Inactivated and live influenza vaccines are approved for children and are safe and efficacious. The absolute effectiveness of vaccines varies by year and is influenced by several factors. The reason for recent reduced performance of live-attenuated influenza vaccines is poorly understood, and active research is ongoing. Vaccination programs are less common in tropical and subtropical countries, where unique logistical and feasibility challenges exist. Antiviral medications for prevention and treatment of influenza in children are an important adjunct to vaccines.