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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 . . .

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.

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.

Background New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. Methods This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18–40 years] followed by 120 toddlers [15–18 months] and 120 infants [9–10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. Discussion This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination. Trial registration Pan-African Clinical Trials Registry 202008836432905 . ClinicalTrials.gov NCT04394689

Lowering the age for receiving the first dose of a measles-containing vaccine (MCV1) has been suggested to close the emerging immunity gap in infants. However, tolerability remains one of the main concerns for vaccine-hesitant parents. We conducted a systematic review and meta-analysis of reactogenicity following MCV1 in infants under 12 months of age. We searched EMBASE and PubMed in February 2021. The search was updated in February 2024. With exception of case reports, we included all English-written original studies published >1985 that contained frequency measures on adverse events (AEs) within 56 days following MCV1 in infants <12 months of age. We identified all common AEs and their frequencies and combined these across studies in a meta-analysis. The effect of measles strain and vaccine valency was also evaluated. We included 24 studies for analysis: 18 randomized controlled trials (RCTs), three interventional studies, and three observational studies. Only one RCT was placebo-controlled. Commonly reported AEs were injection site reactions, fever, rash, gastrointestinal symptoms, respiratory tract symptoms, conjunctivitis, and symptoms related to the general condition of the infant. The frequency of any AE was generally <10 %; however, the placebo-controlled trial showed no difference between MCV1 and placebo-injected infants. Edmonston B strains and measles-mumps-rubella-varicella vaccine (MMRV) were associated with a higher rate of high fever >39 °C. Most AEs occurred in <10 % of infants receiving MCV1 at < 12 months of age. The placebo-controlled trial suggested no excess reactogenicity following early MCV. Measles strain and vaccine valency may affect AE risks, but other factors such as socioeconomic status, race, and setting could also explain this finding, as these were not equally distributed between studies. Caution is advised when interpreting findings from studies without a placebo group.

Vaccine adverse events and controversial safety issues have occurred in recent decades in Japan: aseptic meningitis following the measles-mumps-rubella combined vaccine (MMR), anaphylaxis after immunization with live virus vaccines and inactivated split influenza vaccine, an increased incidence of febrile illness following the simultaneous administration of inactivated vaccines, and chronic pain with neurological illness after immunization with the human papilloma virus vaccine (HPV). Vaccine adverse events are a matter of concern for the public as well as general practitioners; some are within the range of assumptions that adverse reactions after live attenuated vaccines are related to the nature of their parental wild-type viruses. Vaccines stimulate the innate immunity of host immunological defense mechanisms and induce the development of specific acquired immunity. Some adverse events related to autoimmune responses have been reported, such as idiopathic thrombocytopenic purpura and acute disseminated encephalomyelitis (ADEM). Although a plausible relationship was not demonstrated, the possibility of an association cannot be denied. The pathogenicity of adverse reactions was investigated for anaphylactic reactions, systemic and local reactions following vaccinations. Initial innate immune responses are essential for the development of acquired immunity and are related to adverse events from different viewpoints.

•There was no effect of an additional early measles vaccination on severe morbidity.•There was no indication of a differential effect between boys and girls.•A non-significant beneficial effect of MV was seen with no OPV after randomization. Non-specific effects (NSEs) of vaccines have increasingly gained attention in recent years. Recent studies suggest that live vaccines, such as measles vaccine (MV), have beneficial effects on health, while inactivated vaccines, such as the diphtheria-tetanus-pertussis (DTP) vaccine, may have harmful effects. If this is the case, it should improve child health to move MV closer to the last vaccination with DTP. The objective of this study was to investigate the NSEs of an additional early dose of MV on hospitalization or mortality. Children were randomized to receive either the standard MV at 9 months (control) or an additional early dose of MV 4 weeks after the third dose of DTP-containing Pentavalent vaccine and the standard MV at 9 months (intervention). In this analysis of a secondary outcome in the trial, we investigated the effect of the intervention on a composite endpoint of over-night hospitalization with or without recovery, or death without previous hospitalization, in children between 4.5 and 36 months of age in the Nouna HDSS in Burkina Faso. We used Cox proportional hazards regression with repeated events and time since study enrolment as underlying time-scale. Among 2258 children in the intervention and 2238 children in the control group we observed a total of 464 episodes of hospitalization or mortality. There was no difference between intervention and control group (HR = 1.00, 95% Confidence Interval (CI) 0.83–1.20). Results from the per-protocol and intention-to-treat analysis were similar. Although no significant, results suggest a possible beneficial effect of early MV in children that had not been exposed to an OPV campaign after enrolment (HR = 0.83, 95% CI 0.55–1.29). We did not detect any effect of early MV on subsequent hospitalization or mortality. However, possible effects of early MV could have been obscured by NSEs of the frequent OPV campaigns. Registration: The trial was registered at ClinicalTrials.gov, NCT01644721

As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP≥5 mg/l (28 v. 12 %; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95 % CI 1·44, 10·90) but not in males (GMR 0·44; 95 % CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS.

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.

There are increasing reports of outbreaks of measles in countries that achieved measles elimination using two doses of measles-mumps-rubella (MMR) vaccine, particularly in health care settings. While responses to a third dose of MMR in two-dose recipients have been examined, these studies have all administered MMR by the standard (intramuscular or subcutaneous) route, and data on the duration of antibody are limited. We have developed a protocol for an open-label parallel-arm randomized-controlled trial to compare measles antibody responses and safety after intradermal and aerosol administration of MMR with intramuscular, the usual mode of administration in Aotearoa (New Zealand). Eligible participants are aged ≥ 18 years who have previously received two doses of the MMR vaccine and based on levels of IgG antibody to measles or mumps below the threshold for seropositivity in commercially available screening tests are required to receive the MMR vaccine prior to entering health professional training programs at Aotearoa universities. The participants will be randomized to three routes of administration (1:1:1) to receive the MMR vaccine by the intradermal (via microneedle), intrapulmonary (via vibrating mesh nebulizer), or intramuscular routes. The primary objective is to determine the proportion of participants who attain levels of measles IgG antibody above the seroprotective threshold using a multiplex bead-based immunoassay, with those in the lowest quartile validated by plaque neutralization assay, at days 6-8, 13-15, 28-42, and at 12-18 months post-vaccination. Secondary objectives include a fold increase in the geometric mean concentration of IgG antibody from baseline, and systemic and local reactions following delivery of MMR by each method. The trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR; https://www.anzctr.org.au/Default.aspx; trial registration no. ACTRN12623000130662).