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A more convenient delivery system may facilitate increased global use of measles vaccine. In this randomized, controlled trial involving more than 2000 children in India, the immunogenicity of aerosolized vaccine was inferior to that of vaccine delivered subcutaneously. The Global Vaccine Action Plan aims to eliminate measles from at least five World Health Organization (WHO) regions by 2020. 1 A safe and effective injectable measles vaccine has been widely available since 1963, 2 and intensified efforts between 2000 and 2010 reduced measles-related deaths by 74%. 3 Nevertheless, major outbreaks continue, particularly in resource-poor countries that lack investment in health care systems and the health service infrastructure. In these countries, immunization coverage through routine services and mass campaigns remains low. 4 New approaches to measles vaccination could contribute to reaching elimination goals, particularly if they increase coverage, can be administered by people without . . .

Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18–40 years for the adult cohort, 15–18 months for toddlers, or 9–10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0–97·2) seroconverted to measles and 100% (58/58; 93·8–100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2–95·2) and 100% (59/59; 93·9–100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. The safety and immunogenicity data support the accelerated development of the MRV-MNP. Bill & Melinda Gates Foundation.

Typhoid fever, measles, and rubella continue to contribute significantly to childhood morbidity and mortality in India. In line with WHO recommendations for co-administration of Typhoid Conjugate Vaccine (TCV) and measles–rubella (MR) vaccine at 9 months of age, this phase IV, randomized, open-label, multicenter clinical trial was conducted to assess their immunological compatibility and safety when administered concomitantly. A total of 900 healthy Indian infants aged 9–10 months were randomized into three groups: Group A received TCV and MR vaccine concomitantly; Group B received MR on Day 0 and TCV on Day 28; Group C received TCV on Day 0 and MR on Day 28. Subjects were followed for 6 months after concomitant/last vaccination. Seroconversion rates (SC) in Groups A/B/C at Day 28 were 90.2%/75.3%/89.5% for anti-Vi; 80.4%/75.2%/77.7% for anti-measles, and 87.7%/84.0%/85.2% for anti-rubella antibodies. By study end, SC for anti-Vi was 87.1%/71.6%/83.0%, while SC for anti-measles and anti-rubella reached ~90% and ≥98%, respectively, across all groups. Geometric mean titers increased significantly for all antigens, with no evidence of immunological interference. Safety assessments showed adverse events in 23.9%/32.0%/32.7% participants in Group A/B/C. Most adverse events were mild, and only one serious adverse event was reported. These findings support the co-administration of TCV and MR vaccine as a safe and effective strategy.

Background. Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. Methods. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4–6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. Results. In trial I (1993–1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0–.52). In trial II (2003–2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09–.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4–6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07–.64) between 4–6 months and 5 years. Conclusions. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4–6 months (earlier than currently recommended) and a booster dose at 9–12 months of age. Clinical Trials Registration. NCT00168558.

Measles is a highly infectious respiratory disease which causes 122,000 deaths annually. Although measles vaccine is extremely safe and effective, vaccine coverage could be improved by a vaccine that is more easily administered and transported. We developed an inhalable dry powder measles vaccine (MVDP) and two delivery devices, and demonstrated safety, immunogenicity, and efficacy of the vaccine in preclinical studies. Here we report the first clinical trial of MVDP delivered by inhalation. Sixty adult males aged 18 to 45 years, seropositive for measles antibody, were enrolled in this controlled Phase I clinical study. Subjects were randomly assigned in 1:1:1 ratio to receive either MVDP by Puffhaler® or by Solovent™ devices or the licensed subcutaneous measles vaccine. Adverse events (AEs) were recorded with diary cards until day 28 post-vaccination and subjects were followed for 180 days post-vaccination to assess potential serious long term adverse events. Measles antibody was measured 7 days before vaccination and at days 21 and 77 after vaccination by ELISA and a plaque reduction neutralization test. All subjects completed the study according to protocol. Most subjects had high levels of baseline measles antibody. No adverse events were reported. MVDP produced serologic responses similar to subcutaneous vaccination. MVDP was well tolerated in all subjects. Most subjects had high baseline measles antibody titer which limited ability to measure the serologic responses, and may have limited the adverse events following vaccination. Additional studies in subjects without pre-existing measles antibody are needed to further elucidate the safety and immunogenicity of MVDP.

Chikungunya fever is an emerging viral disease and substantial threat to public health. We aimed to assess the safety, tolerability, and immunogenicity of a live-attenuated, measles-vectored chikungunya vaccine (MV-CHIK). In this double-blind, randomised, placebo-controlled and active-controlled phase 2 trial, we enrolled healthy volunteers aged 18–55 years at four study sites in Austria and Germany. Participants were randomly assigned to receive intramuscular injections with MV-CHIK (5 × 104 or 5 × 105 50% tissue culture infectious dose), control vaccine, or measles prime and MV-CHIK, in two different administration regimens. Randomisation was done by use of three-digit randomisation codes in envelopes provided by a data management service. The participants and investigators were masked to treatment assignment, which was maintained by use of sterile saline as a placebo injection. The primary endpoint was immunogenicity, defined as the presence of neutralising antibodies against chikungunya virus, at day 56, which is 28 days after one or two immunisations. The primary endpoint was assessed in all participants who completed the study without major protocol deviations (per-protocol population) and in all randomised participants who received at least one study treatment (modified intention-to-treat population). The safety analysis included all participants who received at least one study treatment. This trial is registered with ClinicalTrials.gov (NCT02861586) and EudraCT (2015-004037-26) and is completed. Between Aug 17, 2016, and May 31, 2017, we randomly assigned 263 participants to receive control vaccine (n=34), MV-CHIK (n=195), or measles prime and MV-CHIK (n=34). 247 participants were included in the per-protocol population. Neutralising antibodies against chikungunya virus were detected in all MV-CHIK treatment groups after one or two immunisations, with geometric mean titres ranging from 12·87 (95% CI 8·75–18·93) to 174·80 (119·10–256·50) and seroconversion rates ranging from 50·0% to 95·9% depending on the dose and administration schedule. Adverse events were similar between groups, with solicited adverse events reported in 168 (73%) of 229 participants assigned to MV-CHIK and 24 (71%) of 34 assigned to control vaccine (p=0·84) and unsolicited adverse events in 116 (51%) participants assigned to MV-CHIK and 17 (50%) assigned to control vaccine (p=1·00). No serious adverse events related to the vaccine were reported. MV-CHIK showed excellent safety and tolerability and good immunogenicity, independent of pre-existing immunity against the vector. MV-CHIK is a promising candidate vaccine for the prevention of chikungunya fever, an emerging disease of global concern. Themis.

The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system. Control of mosquito populations using pesticides is important for malaria elimination, but effects of pesticides on humans aren’t well understood. Here, Prahl et al. show in a cohort of pregnant Ugandan women and their infants that household spraying with bendiocarb affects the fetal immune system and response to vaccination in infancy.

JVC-001 is a new live attenuated measles–mumps–rubella vaccine (measles AIK-C, mumps RIT4385, and rubella Takahashi strains). Two phase 3 studies were conducted, one to verify the non-inferior immunogenicity of JVC-001 versus the approved mumps and measles–rubella vaccines (J301 study) and another to compare the immunogenicity and safety of different titers (J302 study). Both studies were multicenter, randomized, observer-blinded, phase 3 studies. J301 compared the immunogenicity elicited with a single dose of JVC-001 or control vaccines (measles–rubella vaccine + mumps vaccine [Hoshino strain]). J302 was a titer-confirmation study of a single dose of a low- or high-titer formulation of JVC-001. Both studies enrolled healthy Japanese children (aged 1 year) and had a primary efficacy endpoint of seropositive rate on Day 43. Overall, 861 participants completed J301 (JVC-001, n = 429; control, n = 432) and 100 participants completed J302 (low-titer, n = 48; high-titer, n = 52). For measles and rubella virus antibody titer, non-inferiority of JVC-001 was demonstrated: seropositive rates were ≥ 99.5 %. For mumps virus genotype D antibody titer, seropositive rates were 80.6 % (95 % confidence interval 76.5 % to 84.4 %) with JVC-001 and 88.1 % (84.6 % to 91.0 %) with control vaccination. Thus, non-inferiority for mumps virus genotype D antibody titer was not confirmed. Seropositive rates were similar in the low- and high-titer groups. There were no events leading to discontinuation, or cases of aseptic meningitis in either study. Although the non-inferiority of JVC-001 to currently approved vaccines was not demonstrated for the mumps component, clinical significance and consistent efficacy were indicated. Vaccine titer did not affect immunogenicity. JVC-001 is expected to have a lower risk of aseptic meningitis to currently approved vaccines and raised no new safety signals emerged. •JVC-001 is a new MMR vaccine (measles: AIK-C, mumps: RIT4385, rubella: Takahashi).•Comparative clinical trial of JVC-001 was conducted using MR and mumps vaccines.•Non-inferiority of immunogenicity was not demonstrated only against mumps virus.•However, clinical significance and consistent efficacy were indicated for JVC-001.•Different virus doses of JVC-001 did not affect immunogenicity and safety profile.

Observational studies and trials from low-income countries indicate that measles vaccine has beneficial nonspecific effects, protecting against non-measles-related mortality. It is not known whether measles vaccine protects against hospital admissions. Between 2003 and 2007, 6417 children who had received the third dose of diphtheria, tetanus, and pertussis vaccine were randomly assigned to receive measles vaccine at 4.5 months or no measles vaccine; all children were offered measles vaccine at 9 months of age. Using hospital admission data from the national pediatric ward in Bissau, Guinea-Bissau, we compared admission rates between enrollment and the 9-month vaccination in Cox models, providing admission hazard rate ratios (HRRs) for measles vaccine versus no measles vaccine. All analyses were conducted stratified by sex and reception of neonatal vitamin A supplementation (NVAS). Before enrollment the 2 groups had similar admission rates. Following enrollment, the measles vaccine group had an admission HRR of 0.70 (95% confidence interval [CI], .52-. 95), with a ratio of 0.53 (95% CI, .32-. 86) for girls and 0.86 (95% CI, .58-1.26) for boys. For children who had not received NVAS, the admission HRR was 0.53 (95% CI, .34-. 84), with an effect of 0.30 (95% CI, .13-.70) for girls and 0.73 (95% CI, .42-1.28) for boys (P = .08, interaction test). The reduction in admissions was separately significant for measles infection (admission HRR, 0 [95% CI, 0-.24]) and respiratory infections (admission HRR, 0.37 [95% CI, .16-.89]). Early measles vaccine may have major benefits for infant morbidity patterns and healthcare costs.

In China, measles-rubella vaccine and live attenuated SA 14–14–2 Japanese encephalitis vaccine (LJEV) are recommended for simultaneous administration at 8 months of age, which is the youngest recommended age for these vaccines worldwide. We aimed to assess the effect of the co-administration of these vaccines at 8 months of age on the immunogenicity of measles-rubella vaccine. We did a multicentre, open-label, non-inferiority, two-group randomised controlled trial in eight counties or districts in China. We recruited healthy infants aged 8 months who had received all scheduled vaccinations according to the national immunisation recommendations and who lived in the county of the study site. Enrolled infants were randomly assigned (1:1) to receive either measles-rubella vaccine and LJEV simultaneously (measles-rubella plus LJEV group) or measles-rubella vaccine alone (measles-rubella group). The primary outcome was the proportion of infants with IgG antibody seroconversion for measles 6 weeks after vaccination, and a secondary outcome was the proportion of infants with IgG antibody seroconversion for rubella 6 weeks after vaccination. Analyses included all infants who completed the study. We used a 5% margin to establish non-inferiority. This trial was registered at ClinicalTrials.gov (NCT02643433). 1173 infants were assessed for eligibility between Aug 13, 2015, and June 10, 2016. Of 1093 (93%) enrolled infants, 545 were randomly assigned to the measles-rubella plus LJEV group and 548 to the measles-rubella group. Of the infants assigned to each group, 507 in the measles-rubella plus LJEV group and 506 in the measles-rubella group completed the study. Before vaccination, six (1%) of 507 infants in the measles-rubella plus LJEV group and one (<1%) of 506 in the measles-rubella group were seropositive for measles; eight (2%) infants in the measles-rubella plus LJEV group and two (<1%) in the measles-rubella group were seropositive for rubella. 6 weeks after vaccination, measles seroconversion in the measles-rubella plus LJEV group (496 [98%] of 507) was non-inferior to that in the measles-rubella group (499 [99%] of 506; difference −0·8% [90% CI −2·6 to 1·1]) and rubella seroconversion in the measles-rubella plus LJEV group (478 [94%] of 507) was non-inferior to that in the measles-rubella group (473 [94%] of 506 infants; difference 0·8% [90% CI −1·8 to 3·4]). There were no serious adverse events in either group and no evidence of a difference between the two groups in the prevalence of any local adverse event (redness, rashes, and pain) or systemic adverse event (fever, allergy, respiratory infections, diarrhoea, and vomiting). Fever was the most common adverse event (97 [19%] of 507 infants in the measles-rubella plus LJEV group; 108 [21%] of 506 infants in the measles-rubella group). The evidence of similar seroconversion and safety with co-administered LJEV and measles-rubella vaccines supports the co-administration of these vaccines to infants aged 8 months. These results will be important for measles and rubella elimination and the expansion of Japanese encephalitis vaccination in countries where it is endemic. US Centers for Disease Control and Prevention, US Department of Health and Human Services; China–US Collaborative Program on Emerging and Re-emerging Infectious Diseases.