Comparison of a Novel Human Rabies Monoclonal Antibody to Human Rabies Immunoglobulin for Postexposure Prophylaxis: A Phase 2/3, Randomized, Single-Blind, Noninferiority, Controlled Study.

Background: Lack of access to rabies immunoglobulin (RIG) contributes to high rabies mortality. A recombinant human monoclonal antibody (SII RMAb) was tested in a postexposure prophylaxis (PEP) regimen in comparison with a human RIG (HRIG)-containing PEP regimen. Methods: This was a phase 2/3, randomized, single-blind, noninferiority study conducted in 200 participants with World Health Organization category III suspected rabies exposures. Participants received either SII RMAb or HRIG (1:1 ratio) in wounds and, if required, intramuscularly on day 0, along with 5 doses of rabies vaccine intramuscualarly on days 0, 3, 7, 14 and 28. The primary endpoint was the ratio of the day 14 geometric mean concentration (GMC) of rabies virus neutralizing activity (RVNA) as measured by rapid fluorescent focus inhibition test for SII RMAb recipients relative to HRIG recipients. Results: One hundred ninety-nine participants received SII RMAb (n = 101) or HRIG (n = 98) and at least 1 dose of vaccine. The day 14 GMC ratio of RVNA for the SII RMAb group relative to the HRIG group was 4.23 (96.9018% confidence interval [CI], 2.59-6.94) with a GMC of of 24.90 IU/mL (95% CI, 18.94-32.74) for SII RMAb recipients and 5.88 IU/mL (95% CI, 4.11-8.41) for HRIG recipients. The majority of local injection site and systemic adverse reactions reported from both groups were mild to moderate in severity. Conclusions: A PEP regimen containing SII RMAb was safe and demonstrated noninferiority to HRIG PEP in RVNA production. The novel monoclonal potentially offers a safe and potent alternative for the passive component of PEP and could significantly improve the management of bites from suspected rabid animals. Clincical Trials Registration: CTRI/2012/05/002709.

A Phase 3, Double-Blind, Randomized, Active Controlled Study to Evaluate the Safety of MenAfriVac in Healthy Malians.

BACKGROUND: A safe, affordable, and highly immunogenic meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed to control epidemic group A meningitis in Africa. Documentation of the safety specifications of the PsA-TT vaccine was warranted, with sufficient exposure to detect potential rare vaccine-related adverse reactions. METHODS: This phase 3, double-blind, randomized, active controlled clinical study was designed to evaluate the safety--primarily vaccine-related serious adverse events (SAEs)--up to 3 months after administration of a single dose of the PsA-TT vaccine to subjects aged 1-29 years in Mali. Safety outcomes were also compared to those following a single dose of a licensed meningococcal ACWY polysaccharide vaccine (PsACWY). RESULTS: No vaccine-related SAEs occurred during the 3 months of follow-up of 4004 subjects vaccinated with a single dose of PsA-TT. When compared to PsACWY (1996 subjects), tenderness at the injection site appeared to be more frequent in the PsA-TT group. However, rates of local induration, systemic reactions, adverse events (AEs), and SAEs were similar in both groups, and unsolicited AEs and SAEs were all unrelated to the study vaccines. CONCLUSIONS: The study confirmed on a large scale the excellent safety profile of a single dose of PsA-TT when administered to its entire target population of 1-29 years of age. CLINICAL TRIALS REGISTRATION: PACTR ATMR201003000191317.

Antibody Persistence 1-5 Years Following Vaccination With MenAfriVac in African Children Vaccinated at 12-23 Months of Age.

BACKGROUND: Following mass vaccination campaigns in the African meningitis belt with group A meningococcal conjugate vaccine, MenAfriVac (PsA-TT), disease due to group A meningococci has nearly disappeared. Antibody persistence in healthy African toddlers was investigated. METHODS: African children vaccinated at 12-23 months of age with PsA-TT were followed for evaluation of antibody persistence up to 5 years after primary vaccination. Antibody persistence was evaluated by measuring group A serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific IgG enzyme-linked immunosorbent assay (ELISA). RESULTS: Group A antibodies measured by SBA and ELISA were shown to decline in the year following vaccination and plateaued at levels significantly above baseline for up to 5 years following primary vaccination. CONCLUSIONS: A single dose of PsA-TT induces long-term sustained levels of group A meningococcal antibodies for up to 5 years after vaccination. CLINICAL TRIALS REGISTRATION: ISRTCN78147026.

Antibody Persistence at 1 and 4 Years Following a Single Dose of MenAfriVac or Quadrivalent Polysaccharide Vaccine in Healthy Subjects Aged 2-29 Years.

BACKGROUND: Mass vaccination campaigns of the population aged 1-29 years with 1 dose of group A meningococcal (MenA) conjugate vaccine (PsA-TT, MenAfriVac) in African meningitis belt countries has resulted in the near-disappearance of MenA. The vaccine was tested in clinical trials in Africa and in India and found to be safe and highly immunogenic compared with the group A component of the licensed quadrivalent polysaccharide vaccine (PsACWY). Antibody persistence in Africa and in India was investigated. METHODS: A total of 900 subjects aged 2-29 years were followed up for 4 years in Senegal, Mali, and The Gambia (study A). A total of 340 subjects aged 2-10 years were followed up for 1 year in India (study B). In study A, subjects were randomized in a 2:1 ratio, and in study B a 1:1 ratio to receive either PsA-TT or PsACWY. Immunogenicity was evaluated by measuring MenA serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. RESULTS: In both studies, substantial SBA decay was observed at 6 months postvaccination in both vaccine groups, although more marked in the PsACWY group. At 1 year and 4 years (only for study A) postvaccination, SBA titers were relatively sustained in the PsA-TT group, whereas a slight increasing trend, more pronounced among the youngest, was observed in the participants aged <18 years in the PsACWY groups. The SBA titers were significantly higher in the PsA-TT group than in the PsACWY group at any time point, and the majority of subjects in the PsA-TT group had SBA titers ≥128 and group A-specific IgG concentrations ≥2 µg/mL at any point in time in both the African and Indian study populations. CONCLUSIONS: Four years after vaccination with a single dose of PsA-TT vaccine in Africa, most subjects are considered protected from MenA disease. CLINICAL TRIALS REGISTRATION: PsA-TT-003 (ISRCTN87739946); PsA-TT-003a (ISRCTN46335400).

Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans.

BACKGROUND: Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. METHODS: We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay. RESULTS: In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported. CONCLUSIONS: The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.).

Changes in immunological parameters by ageing in rural healthy Indian adults and their associations with sex and lifestyle.

Several factors including sex and lifestyle have been reported to contribute to the age-related alteration of immune functions. The study was undertaken to determine age-related differences in the proportion of peripheral blood mononuclear lymphocytes in the Indian population using blood samples from 67 healthy adults (33 females and 34 males) aged between 20 and 80 years old. In the linear regression analysis to estimate the relationship with age categories, there was a significant increase in the frequency of natural killer cells with ageing, while their cytolytic activity significantly declined. The frequency of CD4+ T cells increased with age, whereas that of CD8+ T cells decreased, resulting in the age-associated increase of the CD4/CD8 ratio. The subsets of B cells did not show any significant relationship with age. Although there were variations between the male and female subgroups in effect size of ageing, the trends were in the same direction in all the parameters. Reduced fat intake was associated with a lower frequency of CD4+ T cells, and higher serum cotinine level was associated with a higher CD4/CD8 ratio. The results indicate that cellular immunity in the Indian population is affected by ageing, while humoral immunity is less susceptible to ageing.

Immunogenicity and lot-to-lot consistency of a ready to use liquid bovine-human reassortant pentavalent rotavirus vaccine (ROTASIIL - Liquid) in Indian infants.

BACKGROUND: A lyophilized bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, Rotasiil®) was licensed in 2016. A liquid formulation of this vaccine (LBRV-PV, Rotasiil - Liquid) was subsequently developed and was tested for non-inferiority to Rotasiil® and for lot-to-lot consistency. METHODS: This Phase II/III, open label, randomized study was conducted at seven sites across India from November 2017 to June 2018. Participants were randomized into four arms; Lots A, B, and C of LBRV-PV and Rotasiil® in 1:1:1:1 ratio. Three doses of study vaccines were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. Non-inferiority of LBRV-PV to Rotasiil was proven if the lower limit two-sided 95% confidence interval (CI) of geometric mean concentration (GMC) ratio was at least 0.5. Lot-to-lot consistency was proven if 95% CI of the GMC ratios of three lots were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: Of the 1500 randomized infants, 1436 infants completed the study. The IgA GMC ratio of LBRV-PV to Rotasiil® was 1.19 (95% CI 0.96, 1.48). The corresponding IgA seropositivity rates were 60.41% (57.41, 63.35) and 52.75% (47.48, 57.97). The IgA GMC ratios among the three LBRV-PV lots were: Lot A versus Lot B: 1.34 (1.03, 1.75); Lot A versus Lot C: 1.22 (0.93, 1.60); and Lot B versus Lot C: 0.91 (0.69, 1.19). The 95% CIs for the GMC ratios were between 0.69 and 1.75. The incidence of solicited reactions was comparable across the four arms. Only one serious adverse event of gastroenteritis event in the Rotasiil® group was causally related. CONCLUSION: The immunological non-inferiority of LBRV-PV against Rotasiil® as well as lot-to-lot consistency of LBRV-PV was demonstrated. LBRV-PV had safety profile similar to Rotasiil®. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov [NCT03474055] and Clinical Trial Registry of India [CTRI/2017/10/010104].

A randomized Phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants.

Rotavirus is the most common cause of moderate-to-severe infant diarrhoea in developing countries, resulting in enormous morbidity, mortality, and economic burden. A bovine-human reassortant pentavalent rotavirus vaccine (BRV-PV) targeting the globally most common strains was developed in India and tested in a randomized, double-blind, placebo-controlled end-point driven Phase III efficacy clinical trial implemented at six sites across India. Infants 6 to 8weeks of age were randomized (1:1) to receive three oral doses of BRV-PV or placebo at 6, 10, and 14weeks of age along with routine vaccines. Home visit surveillance was conducted to detect severe rotavirus gastroenteritis (SRVGE) and safety outcomes until the children reached two years of age. A total of 3749 infants received BRV-PV while 3751 received placebo. At the time of the primary end-point (when the minimum number of cases needed for analysis were accrued) the vaccine efficacy against SRVGE was 36% (95% CI 11.7, 53.6, p=0.0067) in the per protocol (PP) analysis, and 41.9% (95% CI 21.1, 57.3, p=0.0005) in the intent to treat (ITT) analysis. Vaccine efficacy over the entire follow-up period (until children reached two years of age) was 39.5% (95% CI 26.7, 50, p<0.0001) in the PP analysis and 38.8% (95% CI, 26.4, 49, p<0.0001) in the ITT analysis. Vaccine efficacy against the very severe rotavirus cases (VSRVGE, Vesikari score≥16) was 60.5% (95% CI 17.7, 81, p=0.0131) at the time of the primary analysis and 54.7% (95% CI 29.7, 70.8, p=0.0004) for the complete follow-period in the PP population. The incidence of solicited, unsolicited, and serious adverse events were similar in both the vaccine and placebo groups. Likewise, the number of intussusceptions and deaths were similar between both groups. Thus, BRV-PV is an effective, well tolerated and safe vaccine in Indian infants. (Trial registration: Clinical Trials.Gov [NCT 02133690] and Clinical Trial Registry of India [CTRI/2013/05/003667]).

Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

BACKGROUND: A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. METHOD: Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 µg, 25 µg and 50 µg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. RESULTS: JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. CONCLUSION: Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. TRIAL REGISTRATION: Clinical Trial Registry, India CTRI/2010/091/000301.

Correction: Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

[This corrects the article DOI: 10.1371/journal.pone.0117820.].

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 new meningococcal A conjugate vaccine in Indian children aged 2-10 years: a phase II/III double-blind randomized controlled trial.

This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac™, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY(®), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 µg/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 µg/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac™ is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.

Meningococcal group C and w135 immunological hyporesponsiveness in african toddlers.

A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 and 28 days post-booster vaccination with a 1/5 PsACWY dose, respectively, whereas the W135 SBA GMTs of naïve subjects at these time points following vaccination with a 1/5 dose of PsACWY were 861.1 and 14.6, respectively. Similar differences were observed for serogroup C, with SBA GMTs of 99 and 5.9 at 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY, respectively, for naïve subjects, compared to 4.1 and 3.2 for previously vaccinated subjects. Immunologic hyporesponsiveness for groups C and W135 was observed following a full dose of PsACWY vaccine at 12 to 23 months of age and a 1/5 dose of PsACWY 10 months later compared to the case for PsACWY-naïve subjects receiving a 1/5 dose of PsACWY vaccine.

Safety, immunogenicity, and antibody persistence of a new meningococcal group A conjugate vaccine in healthy Indian adults.

We performed a double-blind, randomized, controlled phase I study to assess safety, immunogenicity, and antibody persistence of the new meningococcal group A conjugate vaccine (PsA-TT) in healthy volunteers aged 18-35 years. Of the 74 male subjects enrolled, 24 received the PsA-TT vaccine (Group 1), 25 received the Meningococcal Polysaccharide Vaccine A+C, Pasteur, Lyon, France (Group 2), and 25 received the Tetanus Toxoid Vaccine Adsorbed, SIIL, Pune India (Group 3). No immediate reactions were observed. Local and systemic solicited reactions within 7 days post-vaccination and unsolicited adverse events (AEs) were mild and similar among the three groups and resolved without sequelae. No serious AEs were notified up to 1 year post-vaccination. Four weeks post-vaccination, a slightly higher proportion of Group 1 subjects had a four-fold increase in SBA titers compared to Group 2 subjects (83% versus 72%, p>0.05). SBA GMTs in Groups 2 and 3 were higher than in Group 3 (p<0.05). Serogroup A-specific IgG GMCs were significantly higher in Group 1 than in Groups 2 (p<0.05) and 3 (p<0.05). After 1 year SBA titers were significantly higher in Group 1 than in Group 2 (p<0.05). The new PsA-TT vaccine was shown to be safe, immunogenic, and able to elicit persistent functional antibody titers in adults. This opens the prospective for further development and licensure of this vaccine to eliminate epidemic meningitis in sub-Saharan Africa.