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Background Adolescents with disability have lower vaccination rates than the general population, including HPV vaccination. Understanding the multi-level influences on vaccination in specialist schools is crucial to achieve optimal vaccination coverage and vaccination experiences for adolescents living with disability. Objective To identify and improve understanding of the facilitators and barriers of HPV vaccination among adolescents with intellectual disabilities or autism in Victorian specialist schools to inform strategies to increase vaccination acceptance and uptake. Methods Qualitative interviews with key stakeholders (adolescents with disabilities, parents, school and council immunisation staff) from six specialist schools in Victoria, Australia. Data were analysed thematically. Inductively derived themes were then deductively mapped across the UNICEF ‘Journey to Immunization’ model. Results 32 interviews were conducted with stakeholders (2 adolescents, 7 parents, 13 school staff, 10 council staff). Trust in vaccines was high, but knowledge of the HPV vaccine was limited. Barriers included lack of accessible information for parents, the consent process, behavioural challenges and vaccine-related anxiety among students. The immunisation program in special schools was perceived as convenient, however preparing students for vaccination day and catering to individual student needs were key. Participants expressed a need for more parent information about options and additional support for vaccination outside of the school program. Conclusions Our study identified a range of facilitators and barriers to the school immunisation program for students with disabilities in specialist schools. The next phase of this work will use co-design workshops to build on the suggestions for improvement and opportunities that could be leveraged to improve vaccination uptake.

A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine. We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization. Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group. RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).

Rotavirus vaccines are less effective in high mortality regions. A rotavirus vaccine administered at birth may overcome challenges to vaccine uptake posed by a complex gut microbiome. We investigated the association between the microbiome and vaccine responses following RV3-BB vaccine (G3P[6]) administered in a neonatal schedule (dose 1: 0-5 days), or infant schedule (dose 1: 6-8 weeks) in Indonesia (Phase 2b efficacy study) ( n  = 478 samples/193 infants) (ACTRN12612001282875) and in Malawi (Immunigenicity study) (n = 355 samples/186 infants) (NCT03483116). Vaccine responses assessed using anti-rotavirus IgA seroconversion (IgA), stool shedding of vaccine virus and vaccine take (IgA seroconversion and/or shedding). Here we report, high alpha diversity, beta diversity differences and high abundance of Bacteroides is associated with positive vaccine take and shedding following RV3-BB administered in the neonatal schedule, but not with IgA seroconversion, or in the infant schedule. Higher alpha diversity was associated with shedding after three doses of RV3-BB in the neonatal schedule compared to non-shedders, or the placebo group. High abundance of Streptococcus and Staphylococcus is associated with no shedding in the neonatal schedule group. RV3-BB vaccine administered in a neonatal schedule modulates the early microbiome environment and presents a window of opportunity to optimise protection from rotavirus disease. Here, the authors show that high alpha diversity, differences in beta diversity, and a high abundance of Bacteroides in the gut microbiome are associated with positive vaccine take and stool shedding following administration of RV3-BB vaccine in the neonatal schedule, but not in the infant schedule or placebo groups, suggesting that the early-life gut microbiome provides a gut environment that optimizes the potential for a positive vaccine response.

Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0–5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0–5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55–0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44–0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.

High titres of rotavirus-specific maternal antibodies may contribute to lower rotavirus vaccine efficacy in low- and middle-income countries (LMICs). RV3-BB vaccine (G3P[6]) is based on a neonatal rotavirus strain that replicates well in the newborn gut in the presence of breast milk. This study investigated the association between maternal serum antibodies and vaccine response in infants administered the RV3-BB vaccine. Serum was collected antenatally from mothers of 561 infants enrolled in the RV3-BB Phase II study conducted in Blantyre, Malawi, and analysed for rotavirus-specific serum IgA and IgG antibodies using enzyme-linked immunosorbent assay. Infant vaccine take was defined as cumulative IgA seroconversion (≥3 fold increase) and/or stool vaccine shedding. Maternal IgA or IgG antibody titres did not have a negative impact on vaccine-like stool shedding at any timepoint. Maternal IgG (but not IgA) titres were associated with reduced take post dose 1 (p < 0.005) and 3 (p < 0.05) in the neonatal vaccine schedule group but not at study completion (week 18). In LMICs where high maternal antibodies are associated with low rotavirus vaccine efficacy, RV3-BB in a neonatal or infant vaccine schedule has the potential to provide protection against severe rotavirus disease.

Intussusception (IS) is the most common cause of acute bowel obstruction in infants and young children. Ultrasonography is being increasingly used as the primary investigation for the diagnosis of IS and to guide air or hydrostatic enema reduction. However the accuracy of ultrasonography outside tertiary care settings in developed countries has not been assessed, particularly in Asia where the incidence of IS based on sonographic diagnosis has been reported as the highest in the world. The aim of this study was to evaluate the accuracy of ultrasonography in the diagnosis of acute IS in infants less than 2 years of age in a paediatric hospital in Vietnam. A prospective study was conducted at the National Hospital for Paediatrics, Hanoi, Vietnam, over a 14-month period recruiting patients <2 years of age with IS. Abdominal ultrasonography was performed on each patient and the accuracy of the diagnosis was evaluated against the final diagnosis provided by air enema and/or surgery. A total of 640 infants <2 years of age presented with clinical symptoms and signs of IS. The diagnosis was confirmed in 533 patients via air enema or surgery. Abdominal ultrasonography was 97.5% (466/478) sensitive and 99% (106/107) specific in the detection of IS. Ultrasonography is an accurate, safe and valuable clinical tool in the diagnosis of IS. The use of ultrasonography as a primary investigation for patients with suspected IS prevents unnecessary radiological or surgical procedures being performed, and reduces radiation exposure while maintaining a high level of diagnostic accuracy. These results validate the use of ultrasonography for the diagnosis of IS in a developing country setting.

Rotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P[6] rotavirus vaccine administered in a neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants. We did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi. Healthy infants less than 6 days of age with a birthweight 2·5 to 4·0 kg were randomly assigned (1:1:1:1) into one of four treatment groups: neonatal vaccine group, which included high-titre (1·0 × 107 focus-forming unit [FFU] per mL), mid-titre (3·0 × 106 FFU per mL), or low-titre (1·0 × 106 FFU per mL); and infant vaccine group, which included high-titre (1·0 × 107 FFU per mL) using a computer generated code (block size of four), stratified by birth (singleton vs multiple). Neonates received their three doses at 0–5 days to 10 weeks and infants at 6–14 weeks. Investigators, participant families, and laboratory staff were masked to group allocation. Anti-rotavirus IgA seroconversion and vaccine take (IgA seroconversion and stool shedding) were evaluated. Safety was assessed in all participants who received at least one dose of vaccine or placebo. The primary outcome was the cumulative IgA seroconversion 4 weeks after three doses of RV3-BB in the neonatal schedule in the high-titre, mid-titre, and low-titre groups in the per protocol population, with its 95% CI. With the high-titre group as the active control group, we did a non-inferiority analysis of the proportion of participants with IgA seroconversion in the mid-titre and low-titre groups, using a non-inferiority margin of less than 20%. This trial is registered at ClinicalTrials.gov (NCT03483116). Between Sept 17, 2018, and Jan 27, 2020, 711 participants recruited were randomly assigned into four treatment groups (neonatal schedule high titre n=178, mid titre n=179, low titre n=175, or infant schedule high titre n=179). In the neonatal schedule, cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed in 79 (57%) of 139 participants in the high-titre group, 80 (57%) of 141 participants in the mid-titre group, and 57 (41%) of 138 participants in the low-titre group and at 18 weeks in 100 (72%) of 139 participants in the high-titre group, 96 (67%) of 143 participants in the mid-titre group, and 86 (62%) of 138 of participants in the low-titre. No difference in cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed between high-titre and mid-titre groups in the neonatal schedule (difference in response rate 0·001 [95%CI −0·115 to 0·117]), fulfilling the criteria for non-inferiority. In the infant schedule group 82 (59%) of 139 participants had a cumulative IgA seroconversion 4 weeks after three doses of RV3-BB at 18 weeks. Cumulative vaccine take was detected in 483 (85%) of 565 participants at 18 weeks. Three doses of RV3-BB were well tolerated with no difference in adverse events among treatment groups: 67 (39%) of 170 participants had at least one adverse event in the high titre group, 68 (40%) of 172 participants had at least one adverse event in the mid titre group, and 69 (41%) of 169 participants had at least one adverse event in the low titre group. RV3-BB was well tolerated and immunogenic when co-administered with Expanded Programme on Immunisation vaccines in a neonatal or infant schedule. A lower titre (mid-titre) vaccine generated similar IgA seroconversion to the high-titre vaccine presenting an opportunity to enhance manufacturing capacity and reduce costs. Neonatal administration of the RV3-BB vaccine has the potential to improve protection against rotavirus disease in children in a high-child mortality country in Africa. Bill & Melinda Gates Foundation, Australian Tropical Medicine Commercialisation Grant.

COVID-19 vaccine booster doses counteract waning immunity and vaccine escape by emerging variants. We evaluated long-term immunogenicity and safety of fractional and standard BNT162b2 vaccine booster doses in Mongolia. In this randomised, controlled, non-inferiority trial, adults primed with two doses of ChAdOx1-S, BBIBP-CorV, or Gam-COVID-Vac were randomised (1:1) to receive a 15 μg (fractional dose) or 30 μg (standard dose) BNT162b2 booster. Geometric mean ratios (GMR) of IgG and surrogate virus neutralising test (sVNT) levels (Wuhan-Hu-1 and Omicron BA.1) were compared over 12 months. SARS-CoV-2 infections, and adverse and serious adverse events (SAEs), were documented. ClinicalTrials.gov Identifier: NCT05265065. Of 601 participants randomised between May 27th and September 30th, 2022, 2 (0.3 %) were lost to follow-up and 19 (3.2 %) withdrew by 12 months. IgG levels declined from 28 days to six months, stabilising thereafter. At 12 months, IgG levels were lower in the fractional compared with the standard arm for ChAdOx1-S primed participants (GMR 0.78 [95 % CI 0.63–0.96], p = 0.017). At six and 12 months, the median sVNT inhibition percentages were comparable by study arm and priming strata. Documented SARS-CoV-2 infections occurred in 25 participants (fractional dose arm n = 12; standard dose arm n = 13). From 28 days, 228 undocumented infections (≥ 1.2-fold IgG increase) occurred (fractional arm n = 112; standard arm n = 116). SAEs (n = 41) were balanced between arms, with no severe vaccine-related AEs or SAEs reported. 15 μg and 30 μg BNT162b2 boosters demonstrated comparable immunogenicity and favourable safety. 15 μg BNT162b2 booster doses may improve vaccine acceptability due to lower reactogenicity. •Anti-spike IgG fell from day 28 to six months, then stabilised; 15µg and 30µg arms had comparable IgG at six and 12 months.•Documented SARS-CoV-2 infections were low (4.2 % by 12 months), with minimal differences between study arms.•Undocumented infections were higher in the 15µg than 30µg arm to six months, but similar by study arm at 12 months.•Wuhan-Hu-1 and Omicron BA.1 sVNT inhibition appeared stable and similar between the 15µg and 30µg arms at six and 12 months.•Adverse events were similar by study arm, mostly mild and unrelated to vaccination. No severe vaccine-related events occurred.

To test the sensitivity and specificity of a clinical case definition of acute intussusception in infants to assist health-care workers in settings where diagnostic facilities are not available. Prospective studies were conducted at a major paediatric hospital in Viet Nam (the National Hospital of Pediatrics, Hanoi) from November 2002 to December 2003 and in Australia (the Royal Children's Hospital, Melbourne) from March 2002 to March 2004 using a clinical case definition of intussusception. Diagnosis of intussusception was confirmed by air enema or surgery and validated in a subset of participants by an independent clinician who was blinded to the participant's status. Sensitivity of the definition was evaluated in 584 infants aged<2 years with suspected intussusception (533 infants in Hanoi; 51 in Melbourne). Specificity was evaluated in 638 infants aged<2 years presenting with clinical features consistent with intussusception but for whom another diagnosis was established (234 infants in Hanoi; 404 in Melbourne). In both locations the definition used was sensitive (96% sensitivity in Hanoi; 98% in Melbourne) and specific (95% specificity in Hanoi; 87% in Melbourne) for intussusception among infants with sufficient data to allow classification (449/533 in Hanoi; 50/51 in Melbourne). Reanalysis of patients with missing data suggests that modifying minor criteria would increase the applicability of the definition while maintaining good sensitivity (96-97%) and specificity (83-89%). The clinical case definition was sensitive and specific for the diagnosis of acute intussusception in infants in both a developing country and a developed country but minor modifications would enable it to be used more widely.