ABSTRACT
Combined measles-mumps-rubella (MMR) vaccines produced by GSK (GSK-MMR) and Merck (Merck-MMR) have demonstrated effectiveness and an acceptable safety profile, as documented over decades of post-licensure use in various regions worldwide. In the United States, 2 doses of the MMR vaccine are recommended at the ages of 12-15 months and 4-6 years. All-cause febrile convulsions have the highest incidence at 12-18 months of age, when the first MMR vaccine dose is administered. Because febrile convulsions can also occur rarely after MMR vaccine administration, we reviewed safety data of the GSK-MMR compared to the Merck-MMR vaccine from 4 clinical trials that evaluated a first dose in 12-15-month-olds and 2 clinical trials that evaluated a second dose in ≥4-year-olds. Overall frequencies of febrile convulsions were ≤0.4% across studies and vaccine groups. The frequency of febrile convulsions occurring 7-10 days post-vaccination with the GSK-MMR vaccine (5.7/10,000) was generally consistent with previously published data. The other safety outcomes were similar between the GSK-MMR and Merck-MMR vaccines in both age groups. Hence, as recommended by the Advisory Committee on Immunization Practices, the GSK-MMR vaccine can also be used for routine immunization of children according to the current immunization schedule in the United States to prevent MMR.
Subject(s)
Measles , Mumps , Rubella , Seizures, Febrile , Child , Humans , Infant , Child, Preschool , Measles-Mumps-Rubella Vaccine , Rubella/prevention & control , Mumps/prevention & control , Seizures, Febrile/chemically induced , Seizures, Febrile/epidemiology , Measles/prevention & control , Vaccines, Combined , Antibodies, ViralABSTRACT
A systematic literature review of Medline and Embase databases was conducted to describe rotavirus (RV) vaccine coverage for a complete series, timing of receipt of all doses in the series, and predictors of RV vaccination coverage in the US for two licensed RV vaccines (RV1, RV5). Nine publications were included in the review. RV vaccination coverage rates of under 80% suggest RV vaccines are underutilized relative to the Healthy People 2020 target and other childhood vaccines. About 50-90% of children initiating RV vaccination complete the series and coverage for a complete series is lower for black and Hispanic children (vs. whites), uninsured or Medicaid insured (vs. privately insured), and for foreign-born (vs. US-born) children. Series completion is significantly greater in children receiving DTaP, RV1 (vs. RV5), and for those receiving routine care from a pediatrician. There is a need to design and implement better RV immunization strategies for US children.
Subject(s)
Rotavirus Infections , Rotavirus Vaccines , Rotavirus , Child , Humans , Infant , Rotavirus Infections/epidemiology , Rotavirus Infections/prevention & control , United States , Vaccination , Vaccination Coverage , Vaccines, AttenuatedABSTRACT
BACKGROUND: In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. METHODS: This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6-12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. RESULTS: Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. CONCLUSION: Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.
Subject(s)
Circovirus , Haemophilus Vaccines , Rotavirus Vaccines , Rotavirus , Antibodies, Bacterial , Child , Diphtheria-Tetanus-Pertussis Vaccine/adverse effects , Haemophilus Vaccines/adverse effects , Hepatitis B Vaccines , Humans , Infant , Poliovirus Vaccine, Inactivated , Rotavirus Vaccines/adverse effects , Single-Blind Method , United States , Vaccines, Combined/adverse effects , Vaccines, Conjugate/adverse effectsABSTRACT
BACKGROUND: MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. METHODS: In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. RESULTS: Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. CONCLUSIONS: If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.
Subject(s)
Measles-Mumps-Rubella Vaccine/immunology , Antibodies, Viral , Enzyme-Linked Immunosorbent Assay , Exanthema/etiology , Female , Fever/etiology , Government Regulation , Humans , Infant , Male , Measles/immunology , Measles/prevention & control , Measles-Mumps-Rubella Vaccine/administration & dosage , Measles-Mumps-Rubella Vaccine/adverse effects , Mumps/immunology , Mumps/prevention & control , Rubella/immunology , Rubella/prevention & control , Single-Blind Method , United States , VaccinationABSTRACT
Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (≥ 94.8%), DTaP-HBV-IPV+ HibA (≥ 98.1%) or DTaP-IPV/Hib+ HBV (≥ 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines.
Subject(s)
Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Diphtheria-Tetanus-Pertussis Vaccine/immunology , Haemophilus Vaccines/administration & dosage , Haemophilus Vaccines/immunology , Hepatitis B Vaccines/administration & dosage , Hepatitis B Vaccines/immunology , Immunization, Secondary , Immunogenicity, Vaccine , Poliovirus Vaccine, Inactivated/administration & dosage , Poliovirus Vaccine, Inactivated/immunology , Vaccines, Combined/administration & dosage , Diphtheria/prevention & control , Diphtheria-Tetanus-Pertussis Vaccine/adverse effects , Female , Haemophilus Vaccines/adverse effects , Hepatitis B/prevention & control , Hepatitis B Vaccines/adverse effects , Humans , Immunization Schedule , Infant , Male , Poliomyelitis/prevention & control , Poliovirus Vaccine, Inactivated/adverse effects , Tetanus/prevention & control , United States , Vaccines, Combined/adverse effects , Vaccines, Combined/immunology , Whooping Cough/prevention & controlABSTRACT
This phase III, open-label, randomized study (NCT01978093) evaluated the immunogenicity and safety of co-administered Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (Hib-MenCY-TT) with human rotavirus vaccine (HRV), hepatitis A vaccine (HAV) and 13-valent pneumococcal conjugate vaccine (PCV13). We randomized 600 infants (1:1) to receive 4 doses of Hib-MenCY-TT at 2, 4, 6 and 12-15 months of age or 3 doses of Hib vaccine conjugated to N. meningitidis outer membrane protein complex (Hib-OMP) at 2, 4 and 12-15 months of age. All infants received HRV at 2 and 4 months of age, PCV13 at 2, 4, 6 and 12-15 months of age, HAV at 12-15 and 18-21 months of age, and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months of age. We measured immune responses against HRV, HAV and Hib with enzyme-linked immunosorbent assays, and against MenC/MenY with serum bactericidal assays using human complement. The 4-dose vaccination series with Hib-MenCY-TT induced a robust immune response against Hib, which was non-inferior to that induced by a 3-dose vaccination series with Hib-OMP, and against MenC and MenY. Hib-MenCY-TT did not interfere with immune responses to concomitantly administered HRV, PCV13 and HAV. We did not identify any safety concern. In conclusion, we showed that 4-dose vaccination series with Hib-MenCY-TT during infancy did not interfere with immune responses of co-administered HRV, PCV13 and HAV, induced robust immune responses against Hib, MenC and MenY, and had a clinically acceptable safety profile.
Subject(s)
Haemophilus Vaccines/administration & dosage , Hepatitis A Vaccines/administration & dosage , Immunogenicity, Vaccine , Pneumococcal Vaccines/administration & dosage , Rotavirus Vaccines/administration & dosage , Tetanus Toxoid/administration & dosage , Antibodies, Bacterial/blood , Antibodies, Viral/blood , Female , Haemophilus Vaccines/immunology , Humans , Infant , Male , Serogroup , Tetanus Toxoid/immunology , Vaccines, Combined/administration & dosage , Vaccines, Conjugate/administration & dosage , Vaccines, Conjugate/immunologyABSTRACT
The introduction of vaccination programs against measles, mumps, and rubella (MMR) led to significant global reduction in morbidity and mortality from these diseases. The currently recommended MMR vaccination schedule in the United States of America comprises 2 vaccine doses typically administered at 12-15 months and 4-6 years, respectively. Considering recent outbreaks in the USA, catch-up vaccination with an additional dose of MMR vaccine could contribute to outbreak control and community protection. This phase III, observer-blind, randomized controlled trial (NCT02058563) assessed the immunogenicity and safety of a dose of the MMR-RIT vaccine (Priorix, GSK) compared to MMR II vaccine (control; M-M-R II, Merck&Co Inc.) in ≥7-year-olds who had received ≥1 previous dose of MMR vaccine. We assessed anti-measles, anti-mumps, and anti-rubella antibody geometric mean concentrations (GMCs; primary endpoint) and seroresponse rates (SRRs) at day 42 post-vaccination. Solicited, unsolicited, and serious adverse events (AEs) were recorded. The according-to-protocol cohort for immunogenicity included 869 participants (MMR-RIT: N = 433; MMR II: N = 436). We observed anti-measles, anti-mumps, and anti-rubella antibody GMCs of 1790.2 mIU/mL, 113.5 EU/mL, and 76.1 IU/mL, respectively, and SRRs of 98.8%, 98.4%, and 99.5%, respectively, after a dose of MMR-RIT; non-inferiority compared to MMR II was demonstrated. Both vaccines showed comparable reactogenicity profiles; the most common solicited AEs were injection site redness and pain, and fever (MMR-RIT: 12.2%, 11.8%, and 3.0%; MMR II: 11.7%, 11.5%, and 5.2%, respectively). The dose of MMR-RIT induced robust immune responses that were not inferior to those of MMR II, and was well tolerated.
Subject(s)
Antibodies, Viral/blood , Immunization, Secondary/methods , Immunogenicity, Vaccine , Measles-Mumps-Rubella Vaccine/immunology , Adolescent , Adult , Antibodies, Viral/immunology , Child , Female , Healthy Volunteers , Humans , Immunization Schedule , Immunization, Secondary/adverse effects , Injection Site Reaction/epidemiology , Injection Site Reaction/immunology , Male , Measles/immunology , Measles/prevention & control , Measles/virology , Measles-Mumps-Rubella Vaccine/administration & dosage , Measles-Mumps-Rubella Vaccine/adverse effects , Mumps/immunology , Mumps/prevention & control , Mumps/virology , Rubella/immunology , Rubella/prevention & control , Rubella/virology , Young AdultABSTRACT
As part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 - June 2013 (RV1 and cIPV) and January 2004 - July 2008 (hIPV). Outcomes were identified in the 0-59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self-controlled case series (SCCS) analysis compared convulsion IRs in a 0-7 day post-vaccination period to a 15-30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 - 3.38; hIPV: 2.05, 95% CI: 1.24 - 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 - 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety.
Subject(s)
Product Surveillance, Postmarketing , Respiratory Tract Infections/prevention & control , Rotavirus Infections/prevention & control , Rotavirus Vaccines/administration & dosage , Vaccines, Attenuated/administration & dosage , Administration, Oral , Databases, Factual , Female , Hospitalization , Humans , Incidence , Infant , Insurance, Health , Intussusception/chemically induced , Male , Mucocutaneous Lymph Node Syndrome/chemically induced , Poliovirus Vaccine, Inactivated/administration & dosage , Poliovirus Vaccine, Inactivated/adverse effects , Prospective Studies , Respiratory Tract Infections/virology , Rotavirus Vaccines/adverse effects , Seizures/chemically induced , United StatesABSTRACT
BACKGROUND: Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. METHODS: This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. RESULTS: Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. CONCLUSION: Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.
Subject(s)
Haemophilus Infections/prevention & control , Haemophilus Vaccines/adverse effects , Haemophilus Vaccines/immunology , Antibodies, Bacterial/blood , Bacterial Capsules/immunology , Female , Haemophilus Infections/epidemiology , Haemophilus Infections/immunology , Haemophilus Vaccines/administration & dosage , Haemophilus Vaccines/chemistry , Haemophilus influenzae type b/immunology , Humans , Immunization Schedule , Immunization, Secondary , Immunogenicity, Vaccine , Infant , Male , Tetanus Toxoid/administration & dosage , Tetanus Toxoid/adverse effects , Tetanus Toxoid/immunology , United States/epidemiology , Vaccines, Conjugate/administration & dosage , Vaccines, Conjugate/adverse effects , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunologyABSTRACT
One combined measles-mumps-rubella (MMR) vaccine without Human Serum Albumin (HSA) is currently licensed in the USA (M-M-R II; Merck, USA) and another has been developed (Priorix™ [MMR-RIT, GSK, Belgium]). In this follow-up study, children from USA or Puerto Rico, who had received one dose of M-M-R II or MMR-RIT at 12-15 months of age in the primary study (NCT00861744), were followed-up for 2 y post-vaccination. Anti-measles and anti-rubella antibodies were measured using Enzyme-Linked Immunosorbent Assay (ELISA), and anti-mumps antibodies using ELISA and plaque reduction neutralization (PRN) assays. Serious adverse events (SAEs) were recorded during the entire follow-up. The according-to-protocol (ATP) persistence cohort included 752 children (M-M-R II = 186, MMR-RIT = 566), who received primary vaccination at a mean age of 12.3 ( ± 0.67) months. 104 children were revaccinated with MMR-containing vaccines; therefore, serology results for timepoints after revaccination were excluded from the analysis. Seropositivity for measles (Year 1≥ 98.3%; Year 2≥ 99.4%) and rubella (Year 1≥ 98.9%; Year 2 = 100%) remained as high at Year 2 as at Day 42. Similarly, seropositivity for mumps determined by ELISA (Year 1≥ 90.1%; Year 2≥ 94.1%) and PRN assays (Year 1≥ 87.5%; Year 2≥ 91.7%) persisted. Thirty-three SAEs were recorded in 23 children; 2 SAEs (inguinal adenitis and idiopathic thrombocytopenic purpura) and one SAE (febrile convulsion) were considered as potentially related to MMR-RIT and M-M-R II, respectively. This study showed that antibodies against measles, mumps and rubella persisted for up to 2 y post-vaccination with either MMR vaccine in children aged 12-15 months, and that both vaccines were well-tolerated during the follow-up period.
Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Immunization Schedule , Measles-Mumps-Rubella Vaccine/administration & dosage , Measles-Mumps-Rubella Vaccine/immunology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Enzyme-Linked Immunosorbent Assay , Follow-Up Studies , Humans , Infant , Measles-Mumps-Rubella Vaccine/adverse effects , Neutralization Tests , Puerto Rico , Time Factors , United States , Viral Plaque AssayABSTRACT
Diarrheal diseases (DD) are leading causes of disease burden, death, and disability, especially in children in low-income settings. DD can also impact a child's potential livelihood through stunted physical growth, cognitive impairment, and other sequelae. As part of the Global Burden of Disease Study, we estimated DD burden, and the burden attributable to specific risk factors and particular etiologies, in the Eastern Mediterranean Region (EMR) between 1990 and 2013. For both sexes and all ages, we calculated disability-adjusted life years (DALYs), which are the sum of years of life lost and years lived with disability. We estimate that over 125,000 deaths (3.6% of total deaths) were due to DD in the EMR in 2013, with a greater burden of DD in low- and middle-income countries. Diarrhea deaths per 100,000 children under 5 years of age ranged from one (95% uncertainty interval [UI] = 0-1) in Bahrain and Oman to 471 (95% UI = 245-763) in Somalia. The pattern for diarrhea DALYs among those under 5 years of age closely followed that for diarrheal deaths. DALYs per 100,000 ranged from 739 (95% UI = 520-989) in Syria to 40,869 (95% UI = 21,540-65,823) in Somalia. Our results highlighted a highly inequitable burden of DD in EMR, mainly driven by the lack of access to proper resources such as water and sanitation. Our findings will guide preventive and treatment interventions which are based on evidence and which follow the ultimate goal of reducing the DD burden.
Subject(s)
Diarrhea/epidemiology , Diarrhea/mortality , Global Burden of Disease , Child , Child, Preschool , Cost of Illness , Diarrhea/economics , Disabled Persons , Female , Humans , Male , Mediterranean Region/epidemiology , Quality-Adjusted Life Years , Risk FactorsABSTRACT
In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer's inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products.
Subject(s)
Circovirus/isolation & purification , DNA, Viral/isolation & purification , Drug Contamination , Rotavirus Vaccines/chemistry , Animals , Circovirus/genetics , Humans , Rotavirus Vaccines/standards , Vaccines, Attenuated/chemistry , Vaccines, Attenuated/standardsABSTRACT
OBJECTIVE: Rotavirus is the leading cause of severe diarrhea among children worldwide, killing approximately 600,000 children annually, including 64,800 in the Eastern Mediterranean Region. Safe, effective rotavirus vaccines will be available soon, and accurate disease burden data will be needed to assess the burden of rotavirus and the value of new vaccines and monitor vaccine program impact. METHODS: To identify epidemiologic studies in which rotavirus diagnostics were applied to children with acute gastroenteritis, we performed a systematic literature review. We selected studies that met 4 criteria and extracted rotavirus data on prevalence estimates, strain identification, age distribution of patients, and seasonal trends. RESULTS: Of the 63 published studies with some rotavirus detection data, 29 met inclusion criteria. Among patients with diarrhea, rotavirus was detected in 40% of inpatients and 23% of outpatients. By 3 years of age, 75% of children experienced a documented rotavirus infection. Circulation of rotavirus occurred year-round, and no clear relationship between the timing of the rotavirus peak with either season or latitude was observed. Comparison of country-specific rotavirus detection rates indicated that the proportion of hospitalizations for rotavirus infection increased with income. CONCLUSION: This systematic review of studies of rotavirus diarrhea among children in the countries of the Eastern Mediterranean Region documents that rotavirus is one of the most significant causes of childhood diarrhea in the region. The findings of this review will be used to establish sentinel hospital surveillance in these countries, estimate disease burden, and characterize its epidemiology using common protocols and diagnostics.
Subject(s)
Diarrhea/epidemiology , Diarrhea/virology , Rotavirus Infections/epidemiology , Child , Child, Preschool , Gastroenteritis/epidemiology , Gastroenteritis/virology , Humans , Infant , Mediterranean Region/epidemiologyABSTRACT
BACKGROUND: An oral, live attenuated human rotavirus vaccine, RIX4414 has been developed to prevent rotavirus gastroenteritis. An integrated safety summary of 8 randomized, placebo-controlled, double-blind phase II and III trials of vaccine at potency licensed for use worldwide was performed. METHODS: Healthy 1- to 18-week-old infants (N = 71209) were enrolled to receive 2 doses of RIX4414/placebo according to 0, 1 or 0, 2 month schedules. Solicited (fever, fussiness/irritability, loss of appetite, vomiting, diarrhea, cough/rhinorrhea) and unsolicited adverse events (AEs) were recorded for 8 days and 31 days, respectively, after each dose. Serious adverse events (SAEs) including intussusception and death were collected throughout the entire study periods. Potential imbalances were defined as the 95% confidence interval (CI) for the relative risk (RR) stratified by trials excluding "1." RESULTS: Solicited AEs were evaluated in 3286 RIX4414 vaccinees and 2015 placebo recipients. Among solicited AEs, no imbalance was noted between groups. SAEs, including death and intussusception, were evaluated in 36755 RIX4414 and 34454 placebo recipients. Within 31 days after each dose, no imbalances were noted between the groups for all SAEs (RR = 0.9; 95% CI: 0.81, 1.01), deaths (RR = 1.64; 95% CI: 0.92, 3.02), and intussusception (RR 1.23; 95% CI: 0.41, 3.90). SAEs because of gastrointestinal diseases including diarrhea, gastroenteritis (all cause and due to rotavirus), dehydration, and intestinal ileus occurred significantly less often in RIX4414 than placebo recipients. CONCLUSIONS: Across the phase II and III clinical trials, the reactogenicity and safety profile between RIX4414 and placebo was similar, in particular with no increased risk of intussusception.
Subject(s)
Gastrointestinal Diseases , Intussusception , Rotavirus Infections , Rotavirus/immunology , Vaccines, Attenuated/adverse effects , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/prevention & control , Gastrointestinal Diseases/virology , Humans , Infant , Infant, Newborn , Intussusception/etiology , Intussusception/prevention & control , Randomized Controlled Trials as Topic , Rotavirus Infections/immunology , Rotavirus Infections/prevention & control , Rotavirus Infections/virology , Rotavirus Vaccines , Treatment Outcome , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/therapeutic useABSTRACT
OBJECTIVE: This study was conducted to confirm the absence of immune interference of 2 doses of RIX4414 (Rotarix) on routine infant vaccinations in the United States. STUDY DESIGN: A total of 484 healthy infants aged 6 to 12 weeks were randomly assigned to 1 of 2 groups to receive 3 doses of Pediarix (combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliovirus vaccine [DTaP-HBV-IPV]), Prevnar (7-valent pneumococcal conjugate vaccine [PCV7]), and ActHIB (Haemophilus influenzae type b conjugate vaccine [Hib]) at 2, 4, and 6 months of age with RIX4414 either coadministered at 2 and 4 months (Co-ad) or administered separately at 3 and 5 months (Sep-ad). Serum antibodies were measured 1 month after dose 3 of the DTaP-HBV-IPV, PCV7, and Hib vaccines. RESULTS: Antibody responses to all antigens were similar in infants in both the Co-ad and Sep-ad groups. Seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and poliovirus types 1, 2, and 3 were achieved by >or=97.9% of the infants in both groups. Antipolyribosyl ribitol phosphate antibody levels of >or=1.0 microg/mL were achieved by 88.3% to 89.4% of infants in both groups. In both groups, >or=97.8% of the infants were seropositive for antipertussis antibodies and the 7 pneumococcal serotypes. Predefined criteria for noninferiority between groups were reached for all antigens. CONCLUSIONS: Two doses of RIX4414 coadministered with routine infant vaccines as recommended in the United States (DTaP-HBV-IPV, PCV7, and Hib) did not impair the immune response to any of the coadministered antigens.
Subject(s)
Haemophilus Vaccines/administration & dosage , Immunization Schedule , Meningococcal Vaccines/administration & dosage , Pneumococcal Vaccines/administration & dosage , Tetanus Toxoid/administration & dosage , Vaccines, Attenuated/administration & dosage , Vaccines, Combined/administration & dosage , Vaccines, Conjugate/administration & dosage , Diphtheria-Tetanus-Pertussis Vaccine , Female , Hepatitis B Vaccines , Heptavalent Pneumococcal Conjugate Vaccine , Humans , Infant , Male , Poliovirus Vaccine, Inactivated , Rotavirus Vaccines , United States , Viral InterferenceABSTRACT
OBJECTIVE: To inform policy-makers about introduction of preventive interventions against typhoid, including vaccination. METHODS: A population-based prospective surveillance design was used. Study sites where typhoid was considered a problem by local authorities were established in China, India, Indonesia, Pakistan and Viet Nam. Standardized clinical, laboratory, and surveillance methods were used to investigate cases of fever of >or= 3 days' duration for a one-year period. A total of 441,435 persons were under surveillance, 159,856 of whom were aged 5-15 years. FINDINGS: A total of 21,874 episodes of fever were detected. Salmonella typhi was isolated from 475 (2%) blood cultures, 57% (273/475) of which were from 5-15 year-olds. The annual typhoid incidence (per 100,000 person years) among this age group varied from 24.2 and 29.3 in sites in Viet Nam and China, respectively, to 180.3 in the site in Indonesia; and to 412.9 and 493.5 in sites in Pakistan and India, respectively. Altogether, 23% (96/413) of isolates were multidrug resistant (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole). CONCLUSION: The incidence of typhoid varied substantially between sites, being high in India and Pakistan, intermediate in Indonesia, and low in China and Viet Nam. These findings highlight the considerable, but geographically heterogeneous, burden of typhoid fever in endemic areas of Asia, and underscore the importance of evidence on disease burden in making policy decisions about interventions to control this disease.
Subject(s)
Salmonella typhi/isolation & purification , Typhoid Fever/epidemiology , Adolescent , Adult , Asia/epidemiology , Child , Child, Preschool , Drug Resistance, Multiple, Bacterial , Endemic Diseases , Humans , Middle Aged , Population Surveillance , Prospective Studies , Salmonella typhi/drug effects , Typhoid Fever/blood , Typhoid Fever/microbiology , Typhoid Fever/prevention & controlABSTRACT
We report the coverage, safety, and logistics of a school-based typhoid fever immunization campaign that took place in Hue City, central Vietnam; a typhoid fever endemic area. A cluster-randomized evaluation-blinded controlled trial was designed where 68 schools (cluster) were randomly allocated the single dose Vi polysaccharide vaccine (Typherix) or the active control hepatitis A vaccine (Havrix). A safety surveillance system was implemented. A total of 32,267 children were immunized with a coverage of 57.5%. Strong predictors for vaccination were attending primary schools, peri-urban location of the school, and low family income. Human resources were mainly schoolteachers and the campaign was completed in about 1 month. Most adverse events reported were mild. Safe injection and safe sharp-waste disposal practices were followed. A typhoid fever school-based immunization campaign was safe and logistically possible. Coverage was moderate and can be interpreted as the minimum that could have been achievable because individual written informed consent procedures were sought for the first time in Hue City and the trial nature of the campaign. The lessons learned, together with cost-effectiveness results to be obtained by the end of follow-up period, will hopefully accelerate the introduction of Vi typhoid fever vaccine in Vietnam.
Subject(s)
Immunization Programs/organization & administration , Mass Vaccination , Polysaccharides, Bacterial , School Health Services , Typhoid Fever/prevention & control , Typhoid-Paratyphoid Vaccines , Adolescent , Child , Cluster Analysis , Feasibility Studies , Female , Humans , Male , Polysaccharides, Bacterial/adverse effects , School Health Services/organization & administration , Single-Blind Method , Typhoid-Paratyphoid Vaccines/adverse effects , VietnamABSTRACT
OBJECTIVE: To determine the safety and logistic feasibility of a mass immunization strategy outside the local immunization program in the pediatric population of urban squatter settlements in Karachi, Pakistan. METHODS: A cluster-randomized double blind preventive trial was launched in August 2003 in 60 geographic clusters covering 21,059 children ages 2 to 16 years. After consent was obtained from parents or guardians, eligible children were immunized parenterally at vaccination posts in each cluster with Vi polysaccharide or hepatitis A vaccine. Safety, logistics, and standards were monitored and documented. RESULTS: The vaccine coverage of the population was 74% and was higher in those under age 10 years. No life-threatening serious adverse events were reported. Adverse events occurred in less than 1% of all vaccine recipients and the main reactions reported were fever and local pain. The proportion of adverse events in Vi polysaccharide and hepatitis A recipients will not be known until the end of the trial when the code is broken. Throughout the vaccination campaign safe injection practices were maintained and the cold chain was not interrupted. Mass vaccination in slums had good acceptance. Because populations in such areas are highly mobile, settlement conditions could affect coverage. Systemic reactions were uncommon and local reactions were mild and transient. Close community involvement was pivotal for information dissemination and immunization coverage. CONCLUSION: This vaccine strategy described together with other information that will soon be available in the area (cost/effectiveness, vaccine delivery costs, etc) will make typhoid fever control become a reality in the near future.
ABSTRACT
To identify enteropathogens for vaccine development, we implemented clinic-based surveillance for severe pediatric diarrhea in Egypt's Nile River Delta. Over 2 years, a physician clinically evaluated and obtained stool samples for microbiology from patients with diarrhea and less than 6 years of age. In the first (N = 714) and second clinic (N = 561), respectively, 36% (N = 254) and 46% (N = 260) of children were infected with rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter, or Shigella. When excluding mixed rotavirus-bacterial infections, for the first and second clinic, 23% and 10% had rotavirus-associated diarrhea, and 14% and 17% had ETEC-associated diarrhea, respectively. Campylobacter-associated diarrhea was 1% and 3%, and Shigella-associated diarrhea was 2% and 1%, respectively, for the two clinics. Rotavirus-associated diarrhea peaked in late summer to early winter, while bacterial agents were prevalent during summer. Rotavirus-associated cases presented with dehydration, vomiting, and were often hospitalized. Children with Shigella- or Campylobacter-associated diarrhea reported as watery diarrhea and rarely dysentery. ETEC did not have any clinically distinct characteristics. For vaccine development and/or deployment, our study suggests that rotavirus is of principle concern, followed by ETEC, Shigella, and Campylobacter.