Bharat Biotech International Research Articles

BF.7 Omicron subvariant in India and China: a raising concern - correspondence.

BF.7 Omicron subvariant in India and China: a raising concern - correspondence.

Intranasal COVID-19 vaccine: a modern vaccination approach.

Dear Editor, The emergence of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) which was originally reported to WHO in December 2019 resulted in the coronavirus illness and it was subsequently declared a global coronavirus disease 2019 (COVID-19) pandemic in March 2020. Recurring disease outbreaks repeatedly overloaded the public health sector, infecting over 613 million people and killing more than 6.5 million as of September 20221. As new strains emerge and natural immunity wanes, the population, particularly immunocompromised individuals, stand an increased risk of severe sickness and death due to this disease. Various research advances paved the way for developing multiple COVID-19 vaccines which have been approved to treat and prevent COVID-19. Currently, available COVID-19 vaccines including mRNA vaccines, recombinant adenovirus vaccines, and recombinant protein vaccines that have received Emergency Use Authorization (EUA) and have been subsequently used to immunize millions of people are all administered through intramuscular injection2. Intramuscular vaccines have been designed to induce antibody-mediated and cell-mediated immune responses and minimal to no detectable mucosal immunity at the site of infection. Since the nose and upper respiratory tract are the primary routes for inhalation pathogens like SARS-CoV-2 and are more susceptible to infection,3 the vaccine response generated after intramuscular immunization can leave the upper respiratory tract vulnerable to viral replication and dissemination because these vaccines are inefficient in stimulating immunoglobulin A secretion in mucosal cells2. Alternatively, it has been found recently that the intranasal (IN) vaccines for COVID-19 have shown a promising ability to induce sterilizing mucosal immunity against mucosal pathogens apart from inducing an antibody-mediated immune response and a robust cell-mediated immunity2. A single dose of effective SARS-CoV-2 vaccine via IN route boosts mucosal immunoglobulin A and T-cell responses in both upper and lower respiratory tract, providing almost complete prevention against viral infection, multiplication, and reducing virus shedding via nasal mucosa that acts as a first-line barrier to the virus entrance before spreading into the lungs2. This immediate protection at the site of infection by restricting the viral replication and clearance of SARS-CoV-2 infection reflects the potency of IN COVID-19 vaccines in the alleviation of seeding new cases of COVID-19 amidst the pandemic; hence, preventing even mild cases of illness and inhibiting the virus transmission to other people. In addition, these vaccines are minimally invasive, have a needle-free mode of administration, and are usually in the form of a nasal spray2. Owing to the easy transportation and storage, these vaccines are also more convenient to use2. However, an essential consideration for IN COVID-19 vaccine is its safety. An extremely rare risk of reversion of live attenuated virus into replicating state, regaining its ability to cause disease in the individual has been observed4. With that, the effectiveness of the vaccine is determined by the immunization type chosen and the addition of essential adjuvants. Phase I, II, and III clinical trials were performed to assess the efficacy of IN COVID-19 immunization by two companies; CanSino Biologics, a Chinese pharmaceutical company, and Bharat Biotech International, a biotechnology company headquartered in India, which received approval in their respective countries for its use after gaining successful results5. These companies have created ‘viral vector’ vaccines that use a harmless adenovirus to deliver the genetic material of the SARS-CoV-2 into host cells. Given the severity of the situation where the healthcare systems are challenged globally due to increased COVID-19-related hospitalizations, it is critical to continue developing effective and reliable COVID-19 vaccines in present times. In the context of respiratory pathogens like SARS-CoV-2, IN vaccines’ pros conceivably outweigh their cons, along with offering both localized protection at the site of infection and activating systemic responses as compared with intramuscular vaccines eliciting only systemic responses. Large-scale clinical studies and trials should be conducted to gather further evidence to prove its effectiveness so that the availability of IN COVID-19 vaccines may be made feasible. This vaccine might also serve as an alternative to limited and inadequate vaccine supplies as well as a booster to intramuscular vaccines. Immunization with IN COVID-19 vaccines will hopefully help deal with the persistent COVID-19 pandemic and potential viral contagious diseases that might arise in the future. Ethics approval Not applicable. Sources of funding None. Authors’ contribution All authors contributed equally. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration Unique Identifying number (UIN) None. Guarantor Govinda Khatri.

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

Immunogenicity and reactogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in children aged 2–18 years: interim data from an open-label, non-randomised, age de-escalation phase 2/3 study

BackgroundDespite having milder symptoms than adults, children are still susceptible to and can transmit SARS-CoV-2. Vaccination across all age groups is therefore necessary to curtail the pandemic. Among the available COVID-19 vaccine platforms, an inactivated vaccine platform has the advantage of excellent safety profile across all age groups; hence, we conducted an age de-escalation study to assess the safety, reactogenicity, and immunogenicity of an inactivated COVID-19 vaccine, BBV152 (COVAXIN; Bharat Biotech International, Hyderabad, India), in children aged 2–18 years.MethodsIn this phase 2/3 open-label, non-randomised, multicentre study done in six hospitals in India, healthy children (male or female) aged 2–18 years were eligible for inclusion into the study. Children who had positive SARS-CoV-2 nucleic acid and serology tests at baseline, or any history of previous SARS-CoV-2 infection, or with known immunosuppressive condition were excluded. Children were sequentially enrolled into one of three groups (>12 to ≤18 years [group 1], >6 to 12 years [group 2], or ≥2 to 6 years [group 3]) and administered with adult formulation of BBV152 as two 0·5 mL intramuscular doses on days 0 and 28. Co-primary endpoints were solicited adverse events for 7 days post-vaccination and neutralising antibody titres on day 56, 28 days after the second dose. Immunogenicity endpoints were compared with Biodefense and Emerging Infections, Research Resources Repository (BEI) reference serum samples and from adults who received two doses of BBV152 in the same schedule in a previously reported phase 2 study. The trial is registered with the Clinical Trials Registry, India (CTRI/2021/05/033752) and ClinicalTrials.gov (NCT04918797).FindingsFrom May 27, 2021, to July 10, 2021, we enrolled 526 children sequentially into groups 1 (n=176), 2 (n=175), and 3 (n=175). Vaccination was well tolerated, with no differences in reactogenicity between the three age groups, and no serious adverse events, deaths, or withdrawals due to an adverse event. Local reactions mainly consisted of mild injection site pain in 46 (26%) of 176 participants in group 1, 61 (35%) of 175 in group 2, and 39 (22%) of 175 in group 3 after dose 1; and 39 (22%) of 176 in group 1, 43 of 175 (25%) in group 2, and 14 of 175 (8%) in group 3 after dose 2; there were no cases of severe pain and few reports of other local reactions. After dose 1, the most frequent solicited systemic adverse event was mild-to-moderate fever, reported in eight (5%) of 176 participants in group 1, 17 (10%) of 175 in group 2, and 22 (13%) of 175 in group 3. No case of severe fever was reported, and rates of all fever were all 4% or less after dose 2. Geometric mean titres (GMTs) of microneutralisation antibodies at day 56 in groups 1 (138·8 [95% CI 111·0–173·6]), 2 (137·4 [99·1–167·5]), and 3 (197·6 [176·4–221·4]) were similar to titres in vaccinated adults (160·1 [135·8–188·8]) and with BEI reference serum samples (103·3 [50·3–202·1]). Similar results were obtained using the plaque reduction neutralisation test (PRNT), in which 166 (95%) of 175 participants in group 1, 165 (98%) of 168 in group 2, and 169 (98%) of 172 in group 3 seroconverted at day 56. The GMT ratio of PRNT titres in children and adults was 1·76 (95% CI 1·32–2·33), indicating a superior response in children compared with adults.InterpretationBBV152 was well tolerated in children aged 2–18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated.FundingBharat Biotech International.

A multicenter, single-blind, randomized, phase-2/3 study to evaluate immunogenicity and safety of a single intramuscular dose of biological E’s Vi-capsular polysaccharide-CRM197 conjugate typhoid vaccine (TyphiBEVTM) in healthy infants, children, and adults in comparison with a licensed comparator

ABSTRACT The current scenario of typhoid fever warrants early prevention with typhoid conjugate vaccines in susceptible populations to provide lifelong protection. We conducted a multicenter, single-blind, randomized, Phase 2/3 study to assess the immunogenicity and safety of Biological E’s Typhoid Vi-CRM197 conjugate vaccine (TyphiBEVTM) compared to Vi-TT conjugate vaccine manufactured by Bharat Biotech International Limited (Typbar-TCV; licensed comparator) in healthy infants, children, and adults from India. The study’s primary objective was to assess the non-inferiority of TyphiBEVTM in terms of the difference in the proportion of subjects seroconverted with a seroconversion threshold value of ≥2.0 µg/mL against Typbar-TCV. A total of 622 healthy subjects (311 each in both vaccine groups) were randomized and received the single dose of the study vaccine. The TyphiBEVTM group demonstrated noninferiority compared to the Typbar-TCV group at Day 42. The lower 2-sided 95% confidence interval limit of the group difference was −.34%, which met the non-inferiority criteria of ≥10.0%. The geometric mean concentration (24.79 µg/mL vs. 26.58 µg/mL) and proportion of subjects who achieved ≥4-fold increase in antiVi IgG antibody concentrations (96.95% vs. 97.64%) at Day 42 were comparable between the TyphiBEVTM and Typbar-TCV vaccine groups. No apparent difference was observed in the safety profile between both vaccine groups. All adverse events reported were mild or moderate in intensity in all age subsets. This data demonstrates that TyphiBEVTM is non-inferior to TypbarTCV in terms of immunogenicity, and the overall safety and reactogenicity in healthy infants, children, and adults studied from India was comparable.

Safety and Immunogenicity Outcomes of an Inactivated Viral Vaccine against SARS-CoV-2 (Covaxin®)

Introduction: Bharat Biotech International Ltd in partnership with National Institute of Virology (NIV), has developed an indigenous whole virion inactivated Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) viral vaccine BBV-152 (Covaxin®), formulated with Toll Like Receptors 7/8 agonist Imidazoquinoline (IMDG) molecule adsorbed to alum (Algel). Variety of factors other than environmental ones can affect vaccines efficiency outside the strict setting of clinical trials, like how the vaccine is stored or transported, and even how patients are vaccinated. In addition, the intrinsic capacity of the recipient to respond to a vaccine which is determined by sex, genetic factors, age, psychological stress, nutrition and other diseases are also likely to have an impact. Aim: To determine the safety, reactogenicity and immunogenicity of the inactivated whole virus vaccine (Covaxin®) amongst hospital-based population groups. Materials and Methods: The prospective analytical study was conducted in the Department of Microbiology, Sawai Man Singh Medical College, Jaipur, Rajasthan, India, from January 2021 to March 2021.The study primarily included Healthcare Workers (HCWs) employed at SMS Medical college and attached hospitals. In-vitro quantitative IgG antibodies against SARSCoV-2 spike Receptor Binding Domain (RBD) were measured using Chemiluminescence Immunoassay (CLIA) based Advia centaur SARS-CoV-2 IgG, manufactured by Siemens Pvt Ltd, Munich, Germany, as per manufacture’s instructions. Results: Out of total 223 individuals, 61.88 % (138/223) showed neutralising antibody titre of >1 index value by CLIA, rest 38.12% (85/223) were non reactive i.e., titre <1 index value, after four weeks of receiving first dose of Covaxin®. After 2 to 4 weeks of receiving second dose 84.30% (188/223) showed neutralising antibody titre of >1 index value by CLIA, rest 15.70% (35/223) were non reactive i.e., titre <1 index value. After receiving first dose, 100% (223/223) of the participants developed localised pain and bodyache 33.63% (75/223). None of the participants showed any anaphylactic reaction or any emergency condition just after vaccination. Conclusion: Covaxin® is a well-tolerated vaccine, and induces good humoral response against SARS-CoV-2 with a significant rise in the neutralising antibody titres.

English

BACKGROUND COVID-19 is a serious disease caused by a novel coronavirus known as SARS-CoV-2 (severe acute respiratory syndrome). With a population of 1.38 billion people, India aimed to vaccinate 300 million people in the first phase of the COVID-19 vaccination program by August 2021, including 30 million health workers and frontline workers, as well as 270 million elderly people (over 50 years) and those people with co-morbidities. COVID-19 vaccination has begun in India with two types of vaccines: Covishield (by Serum Institute of India Ltd) and Covaxin (by Bharat Biotech International Ltd), according to the Press Information Bureau. Manufacturers in India have said that they will be able to meet the country's future COVID-19 vaccination needs. Both the vaccines function by priming the immune system with a SARS-CoV-2 spike protein and require two doses. Covaxin uses an inactivated SARS-CoV-2 virus taken from an asymptomatic patient, while Covishield uses a weakened variant of adenovirus. On prime minister Narendra Modi's birthday, which is on the 17th of September 2021, a massive immunization blitz is planned. With the CoWIN website updated every second throughout the day, India has administered 2.25 crore Covid-19 vaccine doses. METHODS The review study was carried out in PGI Chandigarh, with the base of the material accessed online and a few studies conducted recently. We conducted a literature search using the MEDLINE electronic database to identify published studies until Sep 2021. The search was confined to peer-reviewed articles that were published in English and contained an abstract. Reference lists of journal articles were also screened for additional citations fitting our search criteria. CONCLUSIONS We conclude that masks alone are insufficient to provide adequate protection against COVID-19 and that they must be used in conjunction with physical distancing, hand cleanliness, and vaccination to put an end to the global SARS-CoV-2 pandemic. A successful vaccination is safe, efficacious, long-lasting, and deployable to large populations, and one should follow the local health authority's recommendations. KEY WORDS Coronavirus, Vaccine development, Vaccination, Prevention.

Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial

SummaryBackgroundTyphoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up.MethodsWe did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing.FindingsFrom Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9–88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38–123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262–438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously.InterpretationThe final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever.FundingBill & Melinda Gates Foundation.

A study on adverse effect following immunization COVID-19 vaccination Covishield among MBBS student s of a tertiary care institution in a rural area of Chhattisgarh, India

Background: India has granted emergency use authorization to two COVID-19 vaccines, Pune based Serum Institute of India’s Covishield and Hyderabad- based Bharat Biotech International Ltd.’s Covaxin, for the vaccination drive. Once a vaccine is in use, it must be continuously monitored to make sure it continues to be safe. These data will add on in policy making and also help vaccine to be safely tracked throughout its use. In view of above background present study has been conducted to determine adverse effect following immunization.Methods: A cross sectional observational study was conducted among 400 MBBS students of a rural medical college in Chhattisgarh, India from January 2021 to March 2021. Approval was taken from institutional ethical committee and written informed consent was obtained from participants. A semi-open questionnaire was used to estimate the adverse effect following Covishield administration. Data was processed, analysed using SPSS software and information was obtained.Results: Study shows most common adverse effect was pain at injection site (86%), followed by fever (76%). Female received more (69%) treatment compared to male (31%). Almost 100% of subject experienced adverse effect following immunization (AEFI) following first dose administration whereas about 20% only experienced adverse effect following administration of second dose.Conclusions: Pain at injection site was most common adverse effect followed by fever. Adverse effect was four times more with first dose compared to second dose. Female received more treatment compared to male. Majority had fever and pain for 1-2 days only. Thus, it was concluded that vaccine have no serious side effect.

Evidence of Extended Thermo-Stability of Typhoid Polysaccharide Conjugate Vaccines.

Typhoid conjugate vaccines (TCV) are effective in preventing enteric fever caused by Salmonella enterica serovar Typhi in Southeast Asia and Africa. To facilitate vaccination with the Vi capsular polysaccharide–tetanus toxoid conjugate vaccine, Typbar TCV, and allow it to be transported and stored outside a cold chain just prior to administration, an extended controlled-temperature conditions (ECTC) study was performed to confirm the quality of the vaccine at 40 °C for 3 days at the end of its shelf-life (36 months at 2–8 °C). Studies performed in parallel by the vaccine manufacturer, Bharat Biotech International Limited, and an independent national control laboratory (NIBSC) monitored its stability-indicating parameters: O-acetylation of the Vi polysaccharide, integrity of the polysaccharide–protein conjugate, and its molecular size and pH. ECTC samples stored at 40 °C and 45 °C in comparison with control samples stored at 4 °C and 55 or 56 °C, were shown to have stable O-acetylation and pH; only very slight increases in the percentage of free saccharide and corresponding decreases in molecular size were observed. The deoxycholate method for precipitating conjugated polysaccharide was very sensitive to small incremental increases in percentage of free saccharide, in line with storage temperature and duration. This extended ECTC study demonstrated minimal structural changes to the Vi polysaccharide and conjugate vaccine and a stable formulation following extended exposure to elevated temperatures for the desired durations. This outcome supports the manufacturer’s ECTC claim for the vaccine to be allowed to be taken outside the cold chain before its administration.

Salmonella Typhi Vi polysaccharide conjugate vaccine protects infants and children against typhoid fever

The past decade has seen remarkable progress in our understanding of the scale of the global typhoid fever problem,1 the alarming emergence in south Asia of extensively drug-resistant Salmonella enterica serovar Typhi (S Typhi) threatening effective treatment,2 and the WHO prequalification of a typhoid conjugate vaccine,3 a new tool to prevent disease. In The Lancet, Firdausi Qadri and colleagues report the analysis to 18 months of follow-up of a cluster-randomised trial of the WHO prequalified S Typhi Vi polysaccharide tetanus toxoid conjugate vaccine (Vi-TT; Tybar TCV, Bharat Biotech International, Hyderabad, India) among infants and children aged 9 months to younger than 16 years in the densely populated and highly mobile urban area of Mirpur, Dhaka, Bangladesh.

Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: A randomized controlled phase 2 trial

ObjectivesIn 2017, the World Health Organisation (WHO) pre-qualified a single-dose typhoid conjugate vaccine (TCV) and identified TCV co-administration studies as a research priority. Accordingly, we tested co-administration of Typbar TCV® (Bharat Biotech International) with measles-rubella (MR) and yellow fever (YF) vaccines. MethodsWe conducted a randomized, double-blind, and controlled, phase 2 trial in Ouagadougou, Burkina Faso. Healthy children aged 9–11 months were randomized 1:1 to receive TCV (Group 1) or control vaccine (inactivated polio vaccine (IPV), Group 2). Vaccines were administered intramuscularly with routine MR and YF vaccines. Safety was assessed by (1) local and systemic reactions on days 0, 3, and 7; (2) unsolicited adverse events within 28 days; and (3) serious adverse events (SAEs) within six months after immunization. ResultsWe enrolled, randomized, and vaccinated 100 eligible children (49 Group 1 and 51 Group 2). Safety outcomes occurred with similar frequency in both groups: local/solicited reactions (Group 1: 1/49, Group 2: 3/50), systemic/solicited reactions (Group 1: 4/49, Group 2: 9/50), unsolicited adverse events (Group 1: 26/49, Group 2: 33/51), and SAEs (Group 1: 2/49, Group 2: 3/51). TCV conferred robust immunogenicity without interference with MR or YF vaccines. ConclusionTCV can be safely co-administered with MR and YF vaccines to children at the 9-month vaccination visit.

Vaccines are not one size fits all, just like medications: rotavirus vaccine study.

The current global coronavirus disease 2019 pandemic has shown us once again how important vaccination is in controlling and preventing the spread of deadly diseases. Vaccinations are one of the most tried and tested public health measures aimed at the prevention and eventual eradication of various diseases. Many debilitating diseases like polio have been eradicated in countries like India due to effective vaccination strategies. Just like with any other public health initiative, there do exist various challenges for vaccination. Efficacy and correlate of protection studies are crucial in determining which vaccine works best. The rotavirus vaccine (ROTAVAC; Bharat Biotech International Ltd., Hyderabad, India) is one such example where efficacy seen in one geographical and ethnic population is not replicated elsewhere. This has prompted various researchers and pharmaceutical companies to think about customizing vaccines to the individual needs of a particular geographic and ethnic group. In this brief communication, we look at the rotavirus vaccination story and see how it laid down the idea for customized vaccination development and what the future of vaccine development looks like.

Safety and Immunogenicity Trial of an Inactivated SARS-CoV-2 Vaccine-BBV152: A Phase 1, Double-Blind, Randomised Control Trial

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a Toll-Like Receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or 6 μg with alum (Algel).Methods: We conducted a double-blind, randomised, multicentre, controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 healthy adults Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation were randomised equally to receive three vaccine formulations (n=100 each) prepared with 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel, and an Algel only control arm (n=75). Two intramuscular doses of vaccines were administered (twoweeks apart). Primary outcomes were reactogenicity and safety. Secondary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot.Findings: Among 827 participants screened between July 13 and July 30, 2020, 375 participants were randomised. After both doses, the proportion (95%CI) of solicited local and systemic adverse reactions were 17% (10·5, 26·1), 21% (13·8, 30·5), 14% (8·1, 22·7), and 10% (6·9, 23·6) in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, 6 μg with Algel, and control groups, respectively . The most common solicited adverse events were injection site pain, headache, and fatigue. All solicited adverse events were mild (43, 69·3%) or moderate (19, 30·7%) and were more frequent after the first dose. One serious adverse event was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with AlgelIMDG, 6 μg with Algel-IMDG and 6 μg with Algel groups, respectively. CD4 + and CD8 + T cell responses were detected in a subset from both Algel-IMDG groups.Interpretations: BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.Trial Registration Number: Clinicaltrials.gov : NCT04471519 Funding: This work was supported and funded by Bharat Biotech International Limited. Conflict of Interest: This work was supported and funded by Bharat Biotech International Limited. All authors are employees of one of the above-mentioned organisations, with no stock options or incentives. Co-author- K.E is the Chairman and Managing Director of Bharat Biotech.Ethical Approval: The trial was conducted across 11 sites in 9 states in India. The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees and was conducted in compliance with all International Council for Harmonization 114 (ICH) Good Clinical Practice guidelines.

Safety and immunogenicity of co-administration of meningococcal type A and measles–rubella vaccines with typhoid conjugate vaccine in children aged 15–23 months in Burkina Faso

ObjectivesThe World Health Organization pre-qualified single-dose typhoid conjugate vaccine (TCV) and requested data on co-administration with routine vaccines. The co-administration of Typbar TCV (Bharat Biotech International) with routine group A meningococcal conjugate vaccine (MCV-A) and measles–rubella (MR) vaccine was tested. MethodsThis was a double-blind, randomized controlled trial performed in Ouagadougou, Burkina Faso. Children were recruited at the 15-month vaccination visit and were assigned randomly (1:1:1) to three groups. Group 1 children received TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; group 2 children received TCV and MCV-A; group 3 children received MCV-A and control vaccine. Routine MR vaccine was administered to all participants. Safety was assessed at 0, 3, and 7 days after immunization, and unsolicited adverse events and serious adverse events were assessed for 28 days and 6 months after immunization, respectively. ResultsA total of 150 children were recruited and vaccinated. Solicited symptoms were infrequent and similar for TCV and control recipients, as were adverse events (group 1, 61.2%; group 2, 64.0%; group 3, 68.6%) and serious adverse events (group 1, 2.0%; group 2, 8.0%; group 3, 5.9%). TCV generated robust immunity without interference with MCV-A vaccine. ConclusionsTCV can be safely co-administered at 15 months with MCV-A without interference. This novel study on the co-administration of TCV with MCV-A provides data to support large-scale uptake in sub-Saharan Africa.

Safety and Immunogenicity of Co-Administration of Meningococcal Type A and Measles Rubella Vaccines with Typhoid Conjugate Vaccine in Children Aged 15-23 Months in Burkina Faso

Background. The World Health Organization (WHO) pre-qualified a single-dose typhoid conjugate vaccine (TCV) in December 2017. WHO requested data on co-administration of TCV with Expanded Programme on Immunisation vaccines in typhoid-endemic countries. We tested co-administration of Typbar TCV® [Bharat Biotech International] with routine group A meningococcal conjugate vaccine (MCV-A) and measles-rubella (MR) vaccine. Methods: We conducted a double-blind, randomised, controlled trial at Schiphra Protestant Hospital outpatient paediatric clinic, Ouagadougou, Burkina Faso. Children recruited at routine 15-month vaccination visits were randomly assigned (1:1:1) to intramuscularly receive: Group 1) TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; Group 2) TCV and MCV-A; or, Group 3) MCV-A and control vaccine. Routine MR vaccine was administered subcutaneously at day 0 to all participants. The primary outcome was safety, assessed by local and systemic reactions at 0, 3, and 7 days after immunisation; and unsolicited adverse events and serious adverse events 28 days and 6 months after immunisation, respectively. Primary analysis included all participants receiving at least one intramuscular vaccine. Immunogenicity was assessed as a secondary endpoint. ClinicalTrials.gov identifier NCT03614533. Findings: Between December 3, 2018 and February 18, 2019, we recruited and vaccinated 150 children: Group 1 (n=49), Group 2 (n=50), and Group 3 (n=51). Solicited local and systemic symptoms were infrequent and similar for TCV and control recipients, as were adverse events (Group 1: 61·2%, 95% CI 46·2-74·8; Group 2: 64·0%, 95% CI 49·2-77·1; Group 3: 68·6%, 95% CI 54·1-80·9) and serious adverse events (Group 1: 2·0%, 95% CI 0·1-10·9; Group 2: 8·0%, 95% CI 2·2-19·2; Group 3: 5·9%, 95% CI 1·2-16·2). No serious adverse events were related to vaccination. TCV generated robust immunity without interference with MCV-A or MR vaccine. Interpretation: TCV can be safely co-administered with routine MCV-A and MR vaccine. Trial Registration: y. The trial is registered at ClinicalTrials.gov, Identifier NCT03614533. Funding: Bill & Melinda Gates Foundation. Declaration of Interests: The authors have no competing interests to declare. Ethics Approval Statement: The study was approved by ethics committees in Burkina Faso (Comite d’Ethique pour la Recherche en Sante [CERS], Ouagadougou, Burkina Faso) and Maryland, USA (Institutional Review Board, University of Maryland, Baltimore), and by the Regulatory Authority in Burkina Faso (L’Agence Nationale de Regulation Pharmaceutique, Ouagadougou, Burkina Faso).

Team science and the creation of a novel rotavirus vaccine in India: a new framework for vaccine development

Team science and the creation of a novel rotavirus vaccine in India: a new framework for vaccine development

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial

Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0-66·9; p=0·0013) and 56·4% (36·6-70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33-0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.

Use of PCR-based assays for the detection of the adventitious agent porcine circovirus type 1 (PCV1) in vaccines, and for confirming the identity of cell substrates and viruses used in vaccine production

Safety and quality are important issues for vaccines. Whereas reversion to virulence poses a safety risk with live attenuated vaccines, the potential for the presence of adventitious agents is also an issue of vaccine quality. The recent detection or porcine circovirus type 1 (PCV1) in human vaccines has further highlighted the importance of quality control in vaccine production. The purpose of this study was to use a novel conventional PCR to detect PCV1, and subsequently screen materials used in the manufacture of vaccines at Bharat Biotech International Limited, India. The genome or gene fragments of PCV1 were not detected in any of the vaccines and materials tested, including the live attenuated rotavirus vaccine candidate ROTAVAC(®). Further, the identity of the cells and the viruses used as starting materials in the manufacture of these vaccines was confirmed by species-specific PCR or virus-specific RT-PCR, and no cross-contamination was detected in any case. The methods can be applied for regular in-house quality control screening of raw materials and seeds/banks, as well as formulated vaccines.

Immunogenicity and safety study of Indirab: A Vero cell based chromatographically purified human rabies vaccine

A chromatographically purified Vero cell rabies vaccine, Indirab manufactured by Bharat Biotech International Limited, Hyderabad, India was subjected to safety and immunogenicity studies by both intramuscular and intradermal routes of administration in parallel with a reference vaccine, Verorab. A Pre-exposure study was undertaken in 239 subjects by intramuscular (IM) route (Study I), Post-exposure study in 188 patients by intramuscular route (Study II) and Simulated post-exposure study in 134 subjects by intradermal (ID) route (Study III). All subjects in these studies were administered with either the test or the reference vaccine as per WHO approved intramuscular and intradermal regimens. The blood samples were collected on days 0, 14 and 35 in case of Study 1, and days 0, 14, 28 and 90 in case of studies II and III. In all studies both vaccine groups had adequate antibody titers (>0.5 IU/mL) on all days tested post-vaccination and there was no significant difference in the titers observed ( p > 0.05). Some side effects like pain, induration, itching and fever were noted in both vaccine groups in all studies. Both vaccines were well tolerated. Hence it can be concluded that Indirab is as safe and immunogenic as Verorab when administered by both intramuscular and intradermal routes.