Sanjay Lalwani

Immunogenicity of a new routine vaccination schedule for global poliomyelitis prevention: an open-label, randomised controlled trial

BACKGROUND Polio eradication needs a new routine immunisation schedule--three or four doses of bivalent type 1 and type 3 oral poliovirus vaccine (bOPV) and one dose of inactivated poliovirus vaccine (IPV), but no immunogenicity data are available for this schedule. We aimed to assess immunogenicity of this vaccine schedule. METHODS We did an open-label, randomised controlled trial in four centres in India. After informed consent was obtained from a parent or legally acceptable representative, healthy newborn babies were randomly allocated to one of five groups: trivalent OPV (tOPV); tOPV plus IPV; bOPV; bOPV plus IPV; or bOPV plus two doses of IPV (2IPV). The key eligibility criteria were: full-term birth (≥37 weeks of gestation); birthweight ≥2·5 kg; and Apgar score of 9 or more. OPV was administered at birth, 6 weeks, 10 weeks, and 14 weeks; IPV was administered intramuscularly at 14 weeks. The primary study objective was to investigate immunogenicity of the new vaccine schedule, assessed by seroconversion against poliovirus types 1, 2, and 3 between birth and 18 weeks in the per-protocol population (all participants with valid serology results on cord blood and at 18 weeks). Neutralisation assays tested cord blood and sera collected at 14 weeks, 18 weeks, 19 weeks, and 22 weeks by investigators masked to group allocation. This trial was registered with the India Clinical Trials Registry, number CTRI/2013/06/003722. FINDINGS Of 900 newborn babies enrolled between June 13 and Aug 29, 2013, 782 (87%) completed the per-protocol requirements. Between birth and age 18 weeks, seroconversion against poliovirus type 1 in the tOPV group occurred in 162 of 163 (99·4%, 95% CI 96·6-100), in 150 (98·0%, 94·4-99·6) of 153 in the tOPV plus IPV group, in 153 (98·7%, 95·4-99·8) of 155 in the bOPV group, in 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and in 154 (99·4%, 96·5-100) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 2 occurred in 157 (96·3%, 92·2-98·6) of 163 in the tOPV group, 153 (100%, 97·6-100·0) of 153 in the tOPV plus IPV group, 29 (18·7%, 12·9-25·7) of 155 in the bOPV group, 107 (68·6%, 60·7-75·8) of 156 in the bOPV plus IPV group, and in 121 (78·1%, 70·7-84·3) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 3 was achieved in 147 (90·2%, 84·5-94·3) of 163 in the tOPV group, 152 (99·3%, 96·4-100) of 153 in the tOPV plus IPV group, 151 (97·4%, 93·5-99·3) of 155 in the bOPV group, 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and 153 (98·7%, 95·4-99·8) of 155 in the bOPV plus 2IPV group. Superiority was achieved for vaccine regimens including IPV against poliovirus type 3 compared with those not including IPV (tOPV plus IPV vs tOPV alone, p=0·0008; and bOPV plus IPV vs bOPV alone, p=0·0153). 12 serious adverse events occurred (six in the tOPV group, one in the tOPV plus IPV group, three in the bOPV group, zero in the bOPV plus IPV group, and two in the bOPV plus 2IPV group), none of which was attributed to the trial intervention. INTERPRETATION The new vaccination schedule improves immunogenicity against polioviruses, especially against poliovirus type 3. FUNDING WHO, through a grant from Rotary International (grant number 59735).

Invasive pneumococcal disease in children aged younger than 5 years in India: a surveillance study

BACKGROUND Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children younger than 5 years of age in India. We aimed to provide nationally representative data for the pattern of disease due to Streptococcus pneumoniae, trends in the serotype of invasive pneumococci, and invasive pneumococci antimicrobial resistance patterns, in India. METHODS In this prospective hospital-based and retrospective laboratory-based surveillance study, we prospectively enrolled children aged younger than 5 years with suspected or proven invasive pneumococcal disease from 18 hospitals or institutional centres and retrospectively included laboratory-confirmed pneumococcal isolates from ten sentinel laboratories, together representing 11 states in India. Eligibility criteria were fever higher than 38°C without localising symptoms, clinical presentation of suspected meningitis or pneumonia, and evidence of radiographic pneumonia. We cultured blood and other normally sterile body fluids, reconfirmed and serotyped pneumococcal isolates, and established antimicrobial susceptibility using standard study protocols. FINDINGS Between Jan 1, 2011, and June 30, 2015, we enrolled 4377 patients. Among 361 (8%) patients with culture-proven pneumococcal disease, all clinical data were known for 226 (63%); among these patients, 132 (58%) presented with pneumonia, 78 (35%) presented with meningitis, and 16 (7%) had other clinical conditions. 131 (3%) died overall and 29 (8%) patients with invasive pneumococcal disease died. Serotypes 14 (52 [14%] of 361), 1 (49 [14%]), 5 (37 [10%]), and 19F (33 [9%]) were the most common. Penicillin non-susceptibility occurred in isolates from 29 (8%) patients, co-trimoxazole resistance occurred in 239 (66%), erythromycin resistance occurred in 132 (37%), and chloramphenicol resistance occurred in 33 (9%). We found multidrug resistance in 33 (9%) of 361 patients. INTERPRETATION The proportion of positive blood cultures, number of isolates, geographical representation, and data generated over the 4·5 years of the study are representative of data for most of India. Continued surveillance is warranted as the decision to introduce protein conjugated vaccine in India is made. FUNDING GlaxoSmithKline India.

Higher levels of brain derived neurotrophic factor but similar nerve growth factor in human milk in women with preeclampsia

Children born to mothers with preeclampsia have consistently been suggested to be at risk for cognitive and behavioral disorders in later life. Breastfeeding is said to be associated with better neurodevelopment outcomes. Our earlier studies indicated higher levels of docosahexaenoic acid (DHA) in human milk in women with preeclampsia. DHA is known to regulate the expression of neurotrophins and together they play a vital role in neurodevelopment and cognitive performance. The present study examines the levels of maternal plasma and milk neurotrophins [(nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)] in women with preeclampsia and compares them with normotensive women who served as controls. Singleton pregnant women diagnosed with preeclampsia (n = 72) and controls (n = 102) were recruited for this study from Bharati Hospital, Pune. Plasma and milk samples were analyzed for NGF and BDNF levels using the Emax Immuno Assay System using promega kits. Maternal plasma NGF and BDNF levels were lower (p < 0.01 for both) in women with preeclampsia as compared to the control women. Milk NGF levels were similar while milk BDNF levels were higher (p < 0.05) in the preeclampsia group as compared to controls. Plasma NGF levels were positively correlated with milk NGF levels in the control group. Our results indicate the differential regulation of milk NGF and BDNF levels in women with preeclampsia. The present study suggests a role for both NGF and BDNF in human milk for postnatal brain development. Further studies need to examine the associations of DHA and BDNF in human milk with cognition at later ages.

Immunogenicity and safety of an indigenously manufactured reconstituted pentavalent (DTwP-HBV+Hib) vaccine in comparison with a foreign competitor following primary and booster immunization in Indian children.

Objective: An open label, controlled clinical study was conducted in Indian infants aged 6-14 weeks to compare the immunogenicity and safety of a reconstituted pentavalent vaccine (DTwP-HBV+Hib) of Serum Institute of India Ltd (SIIL) with TritanrixHB+Hiberix vaccine of Glaxo Smithkline (GSK). Methods: Eligible infants were randomized to receive three doses of the study / comparator vaccine. The vaccines were reconstituted prior to administration, by mixing DTwP-HBV (liquid) with the Hib (lyophilized) vaccine. IgG antibody titres were assessed by ELISA at baseline and after one month following the 3-dose primary immunization schedule. Safety was evaluated after each dose. Further, safety and immunogenicity was also evaluated following a booster dose in the same cohort of children (aged between 15-24 months). Setting: Tertiary-care hospitals in India Important outcome measures: Immunogenicity and safety following a 3-dose primary vaccination series and a booster vaccination. Results: Post-primary immunization, 100% seroprotection was noted for Diphtheria, Tetanus, Hepatitis B and PRP-Hib components in both the vaccine groups. For pertussis, response was 96.1% in SIIL and 95.4% in GSK group. The overall safety profile as well as persistence of antibodies against all vaccine components up to the time of booster immunization was comparable between the SIIL and GSK groups. A marked rise of all antibody concentrations indicated effective priming. The booster dose was safe, well tolerated with a significant increase in antibody concentrations of all the vaccine antigens in both the groups. Conclusion: DTwP-HBV+Hib vaccine of SIIL was found to be safe and immunogenic. This Indian vaccine compared well with the licensed vaccine and is a cost-effective alternative for incorporating into the immunization schedule of various countries so as to control worldwide Hepatitis B and Hib infections.

Differential oxidative stress levels in mothers with preeclampsia delivering male and female babies

Abstract Objectives: Increased oxidative stress is known to be associated with pregnancy complications like preeclampsia (PE). We hypothesize that increased maternal oxidative stress may differentially affect/program the pregnancy outcome during early postnatal periods in male and female babies. Materials and methods: One-hundred three healthy pregnant women (gestation ≥37 weeks) were recruited for the normotensive control (NC) group and 57 women with term-preeclampsia (T-PE; gestation ≥37 weeks) and 28 women with preterm-preeclampsia (PT-PE; gestation <37 weeks) were also recruited. All infants were followed for anthropometric measurements until six months of age. Results: Higher maternal plasma malondialdehyde (MDA) and erythrocyte superoxide dismutase and glutathione peroxidase (GPx) levels were observed in both T-PE and PT-PE groups. Higher maternal levels of MDA and GPx were seen in mothers delivering male babies in T-PE and PT-PE groups, respectively, as compared to mothers delivering female babies. Babies born to mothers with PT-PE showed poor growth and development on all the anthropometric parameters compared to those born to mothers with T-PE and NC. Conclusion: The altered levels of oxidative stress and antioxidant enzymes in mothers with PE delivering male babies suggest that they may be at higher risk for developing metabolic and neurodevelopmental disorders than female babies.

Effectiveness of an Indian-made Attenuated influenza A(H1N1)pdm 2009 vaccine: A case control study

A live attenuated influenza A(H1N1)pdm 2009 vaccine was developed and distributed in India in 2010. We estimated the vaccine effectiveness (VE) against laboratory-confirmed pandemic H1N1 (pH1N1) infections in patients with influenza-like illness who visited five tertiary care hospitals in Pune, India during June–December 2010. Swab specimens were analyzed for influenza pH1N1 by reverse transcriptase polymerase chain reaction (RT-PCR). VE was estimated using the test-negative case-control study design and logistic regression. A total of 784 patients (253 cases, 531 controls) were analyzed. The unadjusted overall VE was 75.5% (95% confidence interval [CI] 42.1–89.7), while the adjusted VE was 76% (95% CI 42.1–89.7). We conclude that the live attenuated influenza A(H1N1)pdm 2009 vaccine was effective in our study population, which has opened prospects for using this platform for trivalent formulations.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine vaccines in India.

Background: The childhood burden of disease attributable to Streptococcus pneumoniae is particularly high in India. The immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) were compared with 7-valent pneumococcal conjugate vaccine (PCV7) in a randomized, active-controlled, double-blind trial conducted at 12 sites in India. Methods: Healthy infants received PCV13 or PCV7 at 6, 10, and 14 weeks of age (infant series) and at 12 months of age (toddler dose), along with routine pediatric vaccinations. Immunoglobulin G responses against the 13 pneumococcal serotypes were evaluated 1 month after the infant series and after the toddler dose. Pertussis and poliomyelitis immune responses were assessed 1 month after the infant series. Safety and tolerability also were assessed. Results: The immunogenicity results for the 7 common serotypes and the concomitant vaccines (whole-cell pertussis and oral poliovirus) were similar for subjects receiving PCV13 and subjects receiving PCV7. Immune responses to the 6 additional serotypes were higher in the PCV13 group compared with the PCV7 group. PCV13 and PCV7 had similar safety and tolerability profiles. Conclusions: PCV13 has immunogenicity similar to PCV7 in response to the 7 common serotypes, and has generally higher immunogenicity in response to the 6 additional serotypes. PCV13 may provide added protection against pneumococcal disease caused by the additional 6 serotypes and does not interfere with immune responses to whole-cell pertussis and oral poliovirus vaccines. PCV13 has an acceptable safety profile in both infants and toddlers, comparable with that of PCV7.

Immunogenicity, safety and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with the DTPw-HBV/Hib vaccine in Indian infants: a single-blind, randomized, controlled study

In India, pneumococcal diseases are major causes of child mortality, and effective vaccines against Streptococcus pneumoniae are needed. This single-blind, randomized study assessed the immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) co-administered with DTPw-HBV/Hib in Indian infants as 3-dose primary vaccination course. A total of 360 infants were randomized (2:1) to receive either PHiD-CV co-administered with DTPw-HBV/Hib (PHiD-CV group) or a Hib vaccine co-administered with DTPw-HBV (control group) at 6, 10, and 14 weeks of age. For each vaccine pneumococcal serotype, the percentage of infants in the PHiD-CV group with antibody concentrations ≥ 0.2 µg/mL one month after the third vaccine dose was at least 98.3%, except for serotypes 6B (77.7%) and 23F (89.5%), and opsonophagocytic activity titers ≥ 8 were measured in at least 95.7% of infants, except for serotypes 1 (90.5%) and 6B (84.5%). In addition, all the infants in the PHiD-CV group were seroprotected against diphtheria, tetanus, Hib, and hepatitis B or seropositive for antibodies against pertussis and NTHi protein D (except one infant). Incidences of solicited local and general symptoms were comparable between groups, except for fever (axillary temperature ≥ 37.5°C), which seemed to occur more frequently in the PHiD-CV group. In conclusion, PHiD-CV was shown to be immunogenic and well-tolerated when co-administered with DTPw-HBV/Hib in Indian infants. This study has been registered at www.clinicaltrials.gov NCT00814710.

Immunogenicity and safety of early vaccination with two doses of a combined measles-mumps-rubella-varicella vaccine in healthy Indian children from 9 months of age: a phase III, randomised, non-inferiority trial

Objective This study (NCT00969436) compared the immunogenicity and safety of measles-mumps-rubella (MMR) followed by MMR+varicella (V) vaccines to (1) 2 doses of combined MMRV and (2) MMR followed by MMRV, in Indian children. Design Phase III, open, randomised, non-inferiority study. Setting 6 tertiary care hospitals located in India. Participants Healthy participants aged 9–10 months not previously vaccinated against/exposed to measles, mumps, rubella and varicella or without a history of these diseases. Interventions Participants were randomised (2:2:1) to receive 2 doses of either MMRV (MMRV/MMRV group) or MMR followed by MMRV (MMR/MMRV group) or MMR followed by MMR+V (MMR/MMR+V, control group) at 9 and 15 months of age. Antibody titres against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. Main outcome measures To demonstrate non-inferiority of the 2 vaccination regimens versus the control in terms of seroconversion rates, defined as a group difference with a lower bound of the 95% CI >−10% for each antigen, 43 days postdose 2. Parents/guardians recorded solicited local and general symptoms for a 4-day and 43-day period after each vaccine dose, respectively. Results Seroconversion rates postdose 1 ranged from 87.5% to 93.2% for measles, 83.3% to 86.1% for mumps and 98.7% to 100% for rubella across the 3 vaccine groups. The seroconversion rates postdose 2 were 100% for measles, mumps and rubella and at least 95.8% for varicella across the 3 vaccine groups. Non-inferiority of MMRV/MMRV and MMR/MMRV to MMR/MMR+V was achieved for all antigens, 43 days postdose 2. The 3 vaccination regimens were generally well tolerated in terms of solicited local and general symptoms. Conclusions The immune responses elicited by the MMRV/MMRV and MMR/MMRV vaccination regimens were non-inferior to those elicited by the MMR/MMR+V regimen for all antigens. The 3 vaccination schedules also exhibited an acceptable safety profile in Indian children. Trial registration number NCT00969436.

Differential levels of long chain polyunsaturated fatty acids in women with preeclampsia delivering male and female babies

Maternal long chain polyunsaturated fatty acids (LCPUFA) play a key role in fetal growth and development. This study for the first time examines the maternal and cord LCPUFA levels in preeclamptic mothers delivering male and female infants. In this study 122 normotensive control pregnant women (gestation≥37 weeks) and 90 women with preeclampsia were recruited. Results indicate lower maternal plasma docosahexaenoic acid (DHA) levels (p<0.05) in women with preeclampsia delivering male babies as compared to normotensive control women delivering male babies. Similarly, cord nervonic acid levels were lower (p<0.01) in women with preeclampsia delivering male babies as compared to normotensive control group. However, cord nervonic acid levels were comparable in women with preeclampsia and normotensive control women delivering female babies. This data suggests that male babies born to mothers with preeclampsia may be at an increased risk of developing neurodevelopmental disorders as compared to female babies. Future studies need to follow up both male and female children born to mothers with preeclampsia since altered levels of LCPUFA at birth may have differential implications for the growth and development.