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Highlights • Sixteen AEFI cases (21%) with symptom or sign of bleeding were reported in 2016–2018. • Six (38%) had intra-cranial haemorrhage; 14 (88%) had bleeding from injection site. • Only one case (6%) had confirmed history of receiving vitamin K at birth. • Three (19%) were classified as late onset VKDB; 11 (69%) as suspected late onset VKDB. • Nine cases (56%) resulted in death; among cases with VKDB diagnosis, eight (57%) died., Background Surveillance for adverse events following immunization (AEFI) is important to monitor vaccine safety and should lead to appropriate responses to improve health and immunization program. Bleeding following vaccination is not recognized as an important AEFI. Without policy of vitamin K (VK) prophylaxis at birth, vitamin K deficiency bleeding (VKDB) could be an important cause of bleeding in young infants and may manifest as AEFI. Methods We retrospectively analysed all serious AEFI cases that presented with external or internal bleeding reported to Nepal’s AEFI surveillance system during 2016–2018. The cases were classified as VKDB, suspected VKDB or non-VKDB. Results During the period, 16 serious AEFI with symptom or sign of bleeding were reported representing 21.3% of all serious AEFI reported. Cases were between 40 and 94 days of age. The National AEFI Investigation Committee classified all cases as coincidental. Fourteen cases (87.5%) had bleeding from injection site. Median time from vaccination to injection site bleeding was 4.3 h (interquartile range: 2.1–11.6 h). Six cases (37.5%) had intra-cranial haemorrhage. Only one case had confirmed history of receiving VK at birth. Ten cases (62.5%) received appropriate treatment (VK injection; blood transfusion if needed). Based on limited laboratory investigations available, three cases (18.75%) could be classified as late onset VKDB and 11 cases (68.75%) as suspected late onset VKDB. Conclusion VKDB should be suspected in young infants presenting with bleeding including following vaccination, and prompt treatment should be initiated. Bleeding following vaccination should be recognized as an important AEFI as even a small amount of blood loss in young infants can be catastrophic. We posit that this series is a small subset of VKDB cases in Nepal detected through AEFI surveillance system. In countries without policy of VK prophylaxis at birth including Nepal, the policy should be introduced.

Cool water packs are a useful alternative to ice packs for preventing unintentional freezing of vaccines during outreach in some situations. Current guidelines recommend the use of a separate refrigerator for cooling water packs from ambient temperatures to prevent possible heat degradation of adjacent vaccine vials. To investigate whether this additional equipment is necessary, we measured the temperatures that vaccine vials were exposed to when warm water packs were placed next to vials in a refrigerator. We then calculated the effect of repeated vial exposure to those temperatures on vaccine vial monitor status to estimate the impact to the vaccine. Vials were tested in a variety of configurations, varying the number and locations of vials and water packs in the refrigerator. The calculated average percentage life lost during a month of repeated warming ranged from 20.0% to 30.3% for a category 2 (least stable) vaccine vial monitor and from 3.8% to 6.0% for a category 7 (moderate stability) vaccine vial monitor, compared to 17.0% for category 2 vaccine vial monitors and 3.1% for category 7 vaccine vial monitors at a constant 5 °C. The number of vials, number of water packs, and locations of each impacted vial warming and therefore percentage life lost, but the vaccine vial monitor category had a higher impact on the average percentage life lost than any of the other parameters. The results suggest that damage to vaccines from repeated warming over the course of a month is not certain and that cooling water packs in a refrigerator where vaccines are being stored may be a useful practice if safe procedures are established.

Graphical abstract, Highlights • The potential antigen targets are being utilized for the formulation of an effective vaccine. Spike protein is the most utilized antigen target for vaccine development, however other structural and non-structural proteins are also considered potent targets. • Several clinical trials, for the SARS-CoV-2 vaccine, are ongoing. However a varying number of challenges are being encountered during the process of vaccine development, manufacturing, and mass distribution. • Conventional vaccination strategies pose toxicities, novel platforms for SARS-CoV-2 vaccines are proving to be effective and safe in larger clinical trials., The SARS-CoV-2, previously called a novel coronavirus, that broke out in the Wuhan city of China caused a significant number of morbidity and mortality in the world. It is spreading at peak levels since the first case reported and the need for vaccines is in immense demand globally. Numerous treatment and vaccination strategies that were previously employed for other pathogens including coronaviruses are now being been adopted to guide the formulation of new SARS-CoV-2 vaccines. Several vaccine targets can be utilized for the development of the SARS-CoV-2 vaccine. In this review, we highlighted the potential of various antigenic targets and other modes for formulating an effective vaccine against SARS-CoV-2. There are a varying number of challenges encountered during developing the most effective vaccines, and measures for tackling such challenges will assist in fast pace development of vaccines. This review will give a concise overview of various aspects of the vaccine development process against SARS-CoV-2, including 1) potential antigen targets 2) different vaccination strategies from conventional to novel platforms, 3) ongoing clinical trials, 4) varying challenges encountered during developing the most effective vaccine and the futuristic approaches.

Background Launched in 1974, the Expanded Program on Immunization (EPI) is estimated to prevent two-three million deaths annually from polio, diphtheria, tuberculosis, pertussis, measles, and tetanus. Additional lives could be saved through better understanding what influences adherence to the EPI schedule in specific settings. Methods The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study followed cohorts in eight sites in South Asia, Africa, and South America and monitored vaccine receipt over the first two years of life for the children enrolled in the study. Vaccination histories were obtained monthly from vaccination cards, local clinic records and/or caregiver reports. Vaccination histories were compared against the prescribed EPI schedules for each country, and coverage rates were examined in relation to the timing of vaccination. The influence of socioeconomic factors on vaccine timing and coverage was also considered. Results Coverage rates for EPI vaccines varied between sites and by type of vaccine; overall, coverage was highest in the Nepal and Bangladesh sites and lowest in the Tanzania and Brazil sites. Bacillus Calmette-Guérin coverage was high across all sites, 87–100%, whereas measles vaccination rates ranged widely, 73–100%. Significant delays between the scheduled administration age and actual vaccination date were present in all sites, especially for measles vaccine where less than 40% were administered on schedule. A range of socioeconomic factors were significantly associated with vaccination status in study children but these results were largely site-specific. Conclusions Our findings highlight the need to improve measles vaccination rates and reduce delayed vaccination to achieve EPI targets related to the establishment of herd immunity and reduction in disease transmission.

Highlights • Oral vaccines exhibit poor performance in low-income settings. • Enterovirus and Campylobacter carriage are associated with lower OPV immunogenicity. • Enterovirus carriage is associated with lower Rotarix immunogenicity and efficacy., Background Oral polio vaccine (OPV) and rotavirus vaccine (RV) exhibit poorer performance in low-income settings compared to high-income settings. Prior studies have suggested an inhibitory effect of concurrent non-polio enterovirus (NPEV) infection, but the impact of other enteric infections has not been comprehensively evaluated. Methods In urban Bangladesh, we tested stools for a broad range of enteric viruses, bacteria, parasites, and fungi by quantitative PCR from infants at weeks 6 and 10 of life, coincident with the first OPV and RV administration respectively, and examined the association between enteropathogen quantity and subsequent OPV serum neutralizing titers, serum rotavirus IgA, and rotavirus diarrhea. Results Campylobacter and enterovirus (EV) quantity at the time of administration of the first dose of OPV was associated with lower OPV1-2 serum neutralizing titers, while enterovirus quantity was also associated with diminished rotavirus IgA (−0.08 change in log titer per tenfold increase in quantity; P = 0.037), failure to seroconvert (OR 0.78, 95% CI: 0.64–0.96; P = 0.022), and breakthrough rotavirus diarrhea (OR 1.34, 95% CI: 1.05–1.71; P = 0.020) after adjusting for potential confounders. These associations were not observed for Sabin strain poliovirus quantity. Conclusion In this broad survey of enteropathogens and oral vaccine performance we find a particular association between EV carriage, particularly NPEV, and OPV immunogenicity and RV protection. Strategies to reduce EV infections may improve oral vaccine responses. ClinicalTrials.gov Identifier: NCT01375647.

Background Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods. Methods A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children’s Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH. Results A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons. Conclusion PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality.

Bacillus Calmette-Guerin (BCG) vaccination has been reported to protect neonates from non-tuberculous pathogens, but no biological mechanism to explain such effects is known. We hypothesised that BCG produces broad-spectrum anti-microbial protection via a hepcidin-mediated hypoferraemia, limiting iron availability for pathogens.To test this we conducted a trial in 120 Gambian neonates comparing iron status in the first 5-days of life after allocation to: (1) All routine vaccinations at birth (BCG/Oral Polio Vaccine (OPV)/Hepatitis B Vaccine (HBV)); (2) BCG delayed until after the study period (at day 5); and (3) All routine vaccinations delayed until after the study period.Vaccine regime at birth did not significantly impact on any measured parameter of iron metabolism. However, the ability to detect an effect of BCG on iron metabolism may have been limited by short follow-up time and high activation of the inflammatory-iron axis in the study population.

Highlights • MMR vaccination is given to protect against measles, mumps and rubella. • RSV is an important cause of acute lower respiratory infections in young children. • MMR vaccination was associated with 22% lower rate of RSV hospital contacts. • MMR vaccination may reduce the rate or severity of RSV infection., Background The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles–mumps–rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections. Objective To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country. Methods Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14–23 months in all children born in Denmark 1997–2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months. Results The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63–0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66–0.93). The adjusted IRR was 0.74 (95% CI, 0.60–0.92) in males and 0.84 (95% CI, 0.66–1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76–1.24) but the adjusted IRR was 0.70 (95% CI, 0.58–0.85) from one month after MMR vaccination. Conclusions MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted.

Background Although 93% of 12- to 23-month-old children in India receive at least one vaccine, typically Bacillus Calmette–Guerin, only 75% complete the recommended three doses of diphtheria-pertussis-tetanus (DPT, also referred to as DTP) vaccine. Determinants can be different for nonvaccination and dropout but have not been examined in earlier studies. We use the three-dose DPT series as a proxy for the full sequence of recommended childhood vaccines and examine the determinants of DPT nonvaccination and dropout between doses 1 and 3. Methods We analyzed data on 75,728 6- to 23-month-old children in villages across India to study demand- and supply-side factors determining nonvaccination with DPT and dropout between DPT doses 1 and 3, using a multilevel approach. Data come from the District Level Household and Facility Survey 3 (2007–08). Results Individual- and household-level factors were associated with both DPT nonvaccination and dropout between doses 1 and 3. Children whose mothers had no schooling were 2.3 times more likely not to receive any DPT vaccination and 1.5 times more likely to drop out between DPT doses 1 and 3, compared with children whose mothers had 10 or more years of schooling. Although supply-side factors related to availability of public health facilities and immunization-related health workers in villages were not correlated with dropout between DPT doses 1 and 3, children in districts where 46% or more villages had a healthcare subcentre were 1.5 times more likely to receive at least one dose of DPT vaccine compared with children in districts where 30% or fewer villages had subcentres. Conclusions Nonvaccination with DPT in India is influenced by village- and district-level contextual factors over and above individuals’ background characteristics. Dropout between DPT doses 1 and 3 is associated more strongly with demand-side factors than with village- and district-level supply-side factors.

Highlights ► We compared the amounts of otitis media episodes in OPV vs. IPV vaccinated children. ► OPV provides some protection against otitis media. ► The protective effect is strongest at the age of 6–18 months., Background The goal of this study was to evaluate whether a live attenuated poliovirus vaccine (OPV) has clinically relevant interfering effect with non-polio infections causing otitis media in young children. Methods Open trial in which the intervention group (64 children) received OPV at the age of 2, 3, 6 and 12 months. The control group (250 children) received IPV (inactivated polio vaccine) at the age of 6 and 12 months. Clinical symptoms were recorded by a questionnaire at the age of 3, 6, 12, 18 and 24 months. Results Otitis media episodes were less frequent in the OPV than in the control group. A significant difference was seen at the age of 6–18 months (IRR = 0.76 [95% CI 0.59–0.94], P = 0.011) and was particularly clear among children, who attended daycare (IRR 0.37 [95% CI 0.19–0.71], P = 0.003). Conclusions OPV provides some protection against otitis media. This effect may be mediated by viral interference with non-polio viruses.

Highlights • MVA.HIVA vaccine was tested for the first time in HIV-1-exposed infants in Africa. • PedVacc 002 had 99% retention of infants over 48 weeks of follow-up. • MVA.HIVA was safe, but not sufficiently immunogenic. • MVA.HVA did not interfere with routine childhood vaccines except for induction of HBV antibodies. • MVA is well suited as a vaccine vector for infants under 1 year of age., Background A safe, effective vaccine for breastfeeding infants born to HIV-1-positive mothers could complement antiretroviral therapy (ART) for prevention of mother-to-child transmission of HIV-1. To date, only a few HIV-1 vaccine candidates have been tested in infants. Trial design A phase I/II randomized controlled trial PedVacc 002 was conducted to determine the safety and immunogenicity of a single, low dose of MVA.HIVA vaccine delivered intramuscularly to healthy 20-week-old infants born to HIV-1-positive mothers in Nairobi, Kenya. Methods Pregnant HIV-1-positive women in the 2nd/3rd trimester of gestation were enrolled, provided with ART and self-selected their infant-feeding modality. Infants received nevirapine and cotrimoxazole prophylaxis. At 20 weeks of age, eligible HIV-1-negative infants were randomized to vaccine versus no-treatment arms and followed to 48 weeks of age for assessments of vaccine safety, HIV-1-specific T-cell responses and antibodies to routine childhood vaccines. Results Between February and November 2010, 182 mothers were screened, 104 were eligible and followed on ART during pregnancy/postpartum, of whom 73 had eligible infants at 20 weeks postpartum. Thirty-six infants were randomized to vaccine and 37 to no treatment. Eighty-four percent of infants breastfed, and retention at 48 weeks was 99%. Adverse events were rare and similar between the two arms. HIV-1-specific T-cell frequencies in interferon-γ ELISPOT assay were transiently higher in the MVA.HIVA arm (p = 0.002), but not above the threshold for a positive assay. Protective antibody levels were adequate and similar between arms for all routine childhood vaccines except HBV, where 71% of MVA.HIVA subjects compared to 92% of control subjects were protected (p = 0.05). Conclusions This trial tested for the first time an MVA-vectored candidate HIV-1 vaccine in HIV-1-exposed infants in Africa, demonstrating trial feasibility and vaccine safety, low immunogenicity, and compatibility with routine childhood vaccinations. These results are reassuring for use of the MVA vector in more potent prime-boost regimens.