Comparing the meningococcal serogroup C immune response elicited by a tetanus toxoid conjugate quadrivalent meningococcal vaccine (MenACYW-TT) versus a quadrivalent or monovalent C tetanus toxoid conjugate meningococcal vaccine in healthy meningococcal vaccine-naïve toddlers: A randomised, controlled trial.

MenACYW-TT (MenQuadfi®) is a quadrivalent meningococcal tetanus toxoid conjugate vaccine licensed in Europe for use in individuals ≥12 months. This study assessed whether serogroup C immune responses with MenACYW-TT were at least non-inferior, or superior, to those of quadrivalent meningococcal ACWY (MCV4-TT; Nimenrix®) and monovalent meningococcal C (MenC-TT; NeisVac-C®) vaccines in toddlers (12-23 months). In this modified, double-blind Phase III study (NCT03890367), 701 toddlers received one dose of MenACYW-TT (n = 230), MCV4-TT (n = 232) or MenC-TT (n = 239). Serum bactericidal assays with human (hSBA) and baby rabbit (rSBA) complement were used to measure anti-meningococcal serogroup C antibodies at baseline and 30 days post-vaccination. A sequential statistical approach was used for primary and secondary objectives. For the primary objectives, superiority of serogroup C was assessed in terms of hSBA seroprotection rates (defined as titers ≥1:8) and GMTs for MenACYW-TT compared to MCV4-TT, and rSBA GMTs compared to MenC-TT. The safety of all vaccines within 30 days post-vaccination was described. When administered as a single dose to meningococcal vaccine-naïve healthy toddlers the superiority of the MenACYW-TT serogroup C immune response versus MCV4-TT was demonstrated for hSBA GMTs (ratio 16.3 [12.7-21.0]) and seroprotection (difference 10.43% [5.68-16.20]); and versus MenC-TT in terms of rSBA GMTs (ratio 1.32 [1.06-1.64]). The safety profiles of a single dose of MenACYW-TT, MCV4-TT and MenC-TT were similar. In meningococcal vaccine-naïve toddlers, MenACYW-TT induced superior immune responses to serogroup C versus MCV4-TT in terms of hSBA seroprotection and GMTs and versus MenC-TT in terms of rSBA GMTs.

Post-Marketing Surveillance Observational Study of Quadrivalent Meningococcal Diphtheria Toxoid Conjugate Vaccine (MenACWY-DT, MCV4/Menactra®) in the Republic of Korea, 2014-2019.

BACKGROUND: Invasive meningococcal disease is a notifiable disease in the Republic of Korea. The meningococcal (groups A, C, Y, and W) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-DT, Menactra®) was licensed in the Republic of Korea in 2014. This post-marketing surveillance (PMS) observational study aims to assess the safety of MenACWY-DT administration of routine clinical care to individuals aged 9-23 months as a two-dose series at least 3 months apart and to individuals 2-55 years as a single dose. METHODS: The PMS observational study (NCT02864927) included participants aged 9 months to 55 years and who were given MenACWY-DT during routine healthcare visits. The study participants were followed-up for up to 30 days following vaccination (additional time was allowed for the visit or phone call to be conducted). Study outcomes included solicited and unsolicited adverse reactions, unexpected adverse events, and serious adverse events (SAEs). RESULTS: A total of 640 participants 9-23 months of age and 671 participants 2-55 years of age were eligible for safety analysis. Overall, AEs were reported by 35.3% of participants aged < 2 years and 45% of participants aged 2-55 years. Solicited adverse reactions were reported by 21.4% and 17.4% of participants aged < 2 years and 2-55 years, respectively. Unsolicited adverse reactions were reported by 26.1% and 37.9%, respectively. No vaccine-related SAEs occurred during the study. The AEs reported in Korean population were consistent with the known safety profile of MenACWY-DT, and most were of grade 1-2 in severity. CONCLUSIONS: This study did not detect any unanticipated or new safety findings of concern with MenACWY-DT in either of the study age groups, and provides reassurance that MenACWY-DT can be used as part of routine immunization care for the prevention of invasive meningococcal disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02864927.

Safety of a quadrivalent meningococcal conjugate vaccine in healthy subjects aged 9 months to 55 years in Vietnam.

PURPOSE: Meningococcal disease is a major global health concern due to its severe and sudden clinical manifestations, devastating long-term sequelae, and predominance in younger age groups. This study evaluated the safety of a quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D; Menactra) in participants aged 9 months to 55 years in Vietnam. METHODS: This was an open-label, single-arm study conducted between June and December 2016. Participants received one 0.5-mL dose of the vaccine, and those aged 9 to 23 months received a second 0.5-mL dose 3 months later. Participants (or their parents or legal guardians) reported adverse events during the 28 days after each dose. RESULTS: The study included 112 participants aged 9 to 23 months and 112 participants aged 2 to 55 years. Of these 224 participants, 100 (44.6%) had one or more solicited reactions within 7 days following any MenACWY-D dose, mostly injection site pain, lost appetite (in 9 to 23-month-olds), and malaise (in 2 to 55-year-olds). Most solicited reactions were of mild or moderate intensity and resolved within 3 days. Five participants had unsolicited adverse reactions (ARs), two of which (tonsillitis and febrile convulsion), in 9 to 23-month-olds, were considered by the investigator as serious adverse events related to the vaccine. No immediate unsolicited ARs, severe unsolicited nonserious ARs, or unsolicited injection site reactions were reported, and both participants who experienced vaccine-related serious adverse events recovered. CONCLUSION: Consistent with studies in other countries, MenACWY-D had an acceptable safety profile in individuals from Vietnam aged 9 months to 55 years (WHO Universal Trial Number: U1111-1143-9207).

Clinical experience with the inactivated hepatitis A vaccine, Avaxim 80U Pediatric.

INTRODUCTION: Hepatitis A, caused by hepatitis A virus (HAV), is primarily transmitted via the fecal/oral route either through ingestion of contaminated food and water or through direct contact with an infectious person. Prevalence of hepatitis A is strongly correlated with socioeconomic factors, decreasing with increased socio-economic development, access to clean water and sanitation. Vaccination against HAV should be part of a comprehensive plan for the prevention and control of viral hepatitis, either as part of regular childhood immunization programs or with other recommended vaccines for travelers. Areas covered: We present here evidence for the immunogenicity and safety of an inactivated HAV pediatric vaccine (Avaxim® 80U Pediatric, Sanofi Pasteur), indicated for use in children aged 12 months to 15 years. Data evaluated are from trials undertaken during the clinical development of this vaccine, a systematic literature review and post-market pharmacovigilance. Expert opinion: The pediatric HAV vaccine is highly immunogenic and generates long-lasting protection against hepatitis A disease in children. The safety and immunogenicity data presented in this review suggest that the pediatric HAV vaccine is a valuable option in the prevention of HAV infection in children in many areas of the world where the disease remains a healthcare issue.

Post-Marketing Surveillance of Hepatitis A Virus Vaccine (Avaxim® 160U) in South Korea from 2011 to 2015.

INTRODUCTION: Hepatitis A, caused by hepatitis A virus (HAV), is one of the leading causes of acute hepatitis in South Korea. Avaxim® 160U is an inactivated hepatitis A vaccine that has been proven to be highly effective and well tolerated. It is licensed for use in more than 90 countries, and was approved for use in South Korea in 2011. Clinical trial and approval processes may not fully assess the safety and efficacy of a vaccine. Post-marketing surveillance (PMS) aims to provide a complete safety profile of a vaccine in a real-life setting. PMS trials are mandatory in South Korea to retain drug licensure. METHODS: This post-marketing observational study (NCT01838070) was conducted over 4 years at 16 centres in South Korea, and aimed to observe and record all types of adverse events (AE) occurring in an adult population after vaccination with Avaxim® 160U. This included solicited events, unsolicited non-serious events, unexpected events and serious events. RESULTS: Case report forms were collected from 614 vaccinees, all of whom completed 30 days of follow-up post-vaccination, of whom 36 (5.9%) experienced 53 solicited and unsolicited AEs, 17 (2.8%) experienced 22 of the solicited AEs, while there were no reports of AEs of severe intensity. A total of 31 unsolicited AEs were reported in 22 patients (3.6%), and no unexpected adverse drug reactions were reported. CONCLUSION: No new safety issues were identified and the safety profile obtained from this study was comparable to that of previous studies for HAV vaccine. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01838070. FUNDING: Sanofi Pasteur.

Safety of two doses of an inactivated hepatitis a vaccine given 6 months apart in healthy toddlers, children, and adolescents aged 12 months to 15 years in China: a phase IV study.

Hepatitis A is a vaccine-preventable infection caused by the HA virus (HAV) with transitional to intermediate endemicity in China. An inactivated vaccine first licensed in China in 2010 (Avaxim® 80U Pediatric) is indicated for primary and booster vaccination in children from 12 months to 15 years of age. This Phase IV, open-label, single-arm trial supported licensure in pediatric age groups in China. A total of 355 healthy infants and toddlers (< 2 years of age), children (2 to 11 years of age), and adolescents (≥ 12 years of age) were enrolled to receive two doses of intramuscular HA vaccine, separated by 6 months. Participants were split into Group 1 (infants and toddlers: N = 270) and Group 2 (children and adolescents: N = 85). Safety was assessed by solicited injection site and systemic adverse events (AEs) for 7 days and unsolicited AEs for 30 days after each vaccination. Serious AEs (SAEs) were collected throughout. Immunogenicity was not assessed. Analyses were descriptive. Both vaccinations were very well tolerated in each group. The incidence of solicited injection site reactions was lower in Group 1 (17.9%) than Group 2 (33.3%) and for solicited systemic reactions was similar for each group. The incidence of unsolicited AEs in Group 1 was 6.3% and none in Group 2. For solicited and unsolicited AEs the incidence was slightly higher after the first vaccination. There were no SAEs. Overall, the good safety profile of this pediatric HA vaccine was confirmed in infants, toddlers, children, and adolescents aged 12 months to 15 years in China.

Bivalent oral cholera vaccine in participants aged 1 year and older in the Dominican Republic: A phase III, single-arm, safety and immunogenicity trial.

The Dominican Republic, historically non-endemic for cholera, is experiencing an ongoing cholera epidemic. We assessed the safety and immunogenicity of two doses of the killed bivalent (O1 and O139) whole-cell oral cholera vaccine (OCV) on day (D)0 and D14 in healthy participants aged ≥1 year. Immediate unsolicited systemic adverse events (AEs) were monitored up to 30 minutes and solicited systemic reactions, up to 7 days after each vaccination. Unsolicited AEs were recorded up to D14 (post-dose 1) and 30 days post-dose 2. A vibriocidal antibody assay with microtiter technique was used to measure serum antibodies to V. cholerae strains (O1 El Tor Inaba, O1 El Tor Ogawa, O139) on D0, D14 and D28. Geometric mean titers (GMTs) and seroconversion (≥4-fold increase from D0) rates were calculated. We recruited 336 participants; 112 in three age groups (1-4, 5-14 and ≥15 years). No safety concerns were observed. GMTs increased from baseline for all serotypes, with marked increases for O1 Inaba and Ogawa post-dose 1. Post-dose 2 GMTs tended to be equal or slightly lower, with ranges: O1 Inaba, 283 (95% confidence interval 191-419) to 612 (426-880); O1 Ogawa, 346 (223-536) to 754 (553-1028); and O139, 20.3 (13.5-30.6) to 43.8 (30.1-63.7). Seroconversion rates post-dose 2 for O1 Inaba and Ogawa were high (≥87%) for all age groups. OCV demonstrated an acceptable safety profile and robust immunogenicity in these participants, in-line with previous observations in epidemic and endemic settings.This study is registered on www.clinicaltrials.gov (NCT02434822).

Safety and Immunogenicity of Two Doses of a Quadrivalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine in Indian and Russian Children Aged 9 to 17 Months.

OBJECTIVE: Evaluation of tolerability, safety and immunogenicity of a two-dose series of a quadrivalent meningococcal polysaccharide diptheria toxoid conjugate (ACYW-D) vaccine in Indian and Russian infants/toddlers. DESIGN: Open-label, single-arm, phase III multi-national trial. STUDY PARTICIPANTS: 300 children aged 9-17 months, previously unvaccinated against meningococcal disease from four sites each in India (n=200) and the Russian Federation (n=100). INTERVENTION: Two 0.5 mL doses of ACYW-D by intramuscular injection, 3-6 months apart. MAIN OUTCOME MEASURES: Meningococcal antibody titers to serogroups A, C, W-135 and Y, determined using a serum bactericidal assay in the presence of human complement before vaccination and 28 days after the second vaccination. Titers ≥1:8 against either/all of the A, C, W-135 or Y were considered sero-protective. RESULTS: After dose 2, 95.7-99.5% and 92.9-99.0% of infants/toddlers achieved seroprotection across the four serogroups in India and the Russian Federation, respectively. No immediate adverse events were reported after any dose of ACYW-D. Solicited reactions were reported in 49.2% of participants, and were mainly of Grade 1 severity, and resolved within three days. Unsolicited adverse events were reported in 19.1% of infants: one event (Grade 3 diarrhea, resolving within one day) was considered related to study vaccine. No non-serious adverse events led to premature withdrawal from the study. Four serious adverse events were reported; none were considered related to study vaccine. No deaths occurred during the study. CONCLUSIONS: A two-dose series of ACYW-D vaccine in Indian and Russian children (9-17 month) was well-tolerated with no safety concerns, and induced robust bactericidal antibody responses against the meningococcal serogroups contained in the vaccine.

Seven-year follow-up of the immune response after one or 2 doses of inactivated hepatitis A vaccine given at 1 year of age in the Mendoza Province of Argentina.

This monocenter, descriptive, prospective, non-interventional study evaluated the long-term immune responses following routine vaccination with one or 2 doses of a licensed inactivated hepatitis A (HA) vaccine (Avaxim® 80U Pediatric) at age 11-23 months in a cohort of children from Mendoza, Argentina. Antibodies to hepatitis A virus (anti-HAV) were quantified annually up to Y5, and at Y7. Children whose titer decreased to below the seroprotection threshold (defined as an anti-HAV antibody concentration of ≥ 10 mIU/mL in a microparticle enzyme immunoassay up to Y5, or ≥ 3 mIU/mL in an electrochemiluminescence immunoassay at Y7) received a routine booster dose of the same HA vaccine. This report summarizes the data at 7 year after the first vaccination. Of 546 participants initially included, 264 participants remained at Y7 and provided blood samples. Of these, 204 having received one HA primary dose as a toddler were still seroprotected at Y7; titers for a further 7 also having received one HA dose as a toddler fell to below the seroprotection threshold and they therefore received a booster; all 53 having received 2 HA doses as a toddler and still present at Y7 remained seroprotected at Y7. One or 2 primary doses of this HA vaccine in toddlers result in very good persistence of anti-HAV up to 7 year post-first vaccination.

Safety and immunogenicity of the killed bivalent (O1 and O139) whole-cell cholera vaccine in the Philippines.

The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.