ABSTRACT
Objective: To evaluate the incidence of adverse events following administration of an Inactivated poliomyelitis vaccine (IPV) manufactured by Serum Institute of India Pvt. Ltd., Pune, India.
Methods: A single 0.5 ml dose of the IPV was administered intramuscularly to children attending private clinics or out-patient department of hospitals for routine immunization across different cities in India. They were observed over a period of 30 d for local or systemic adverse events and rare case of anaphylaxis, if any.
Results: A total of 2210 children were enrolled of which 2120 children received the vaccine within primary immunization series and 90 children received booster dose. The common adverse events reported were pain, erythema, swelling and fever. No serious adverse event was reported during the study period.
Conclusions: Poliomyelitis vaccine (Inactivated) manufactured by Serum Institute of India Pvt. Ltd., Pune can be safely administered to children following the Expanded Programme on Immunization or World Health Organization recommended immunization schedule.
Introduction
Polio is a crippling and potentially fatal infectious disease which mainly affects children under 5 y of age. Historically, India has been the largest endemic reservoir of polio in the world with 50,000 to 100,000 paralytic polio cases reported each year between 1978 and 1995. However, since 13 January 2011, not even a single case of wild poliovirus has been reported in India indicating that, polio is no longer endemic in India. Being a polio free country is a notable milestone for India, and this was possible because of successful immunization and awareness campaigns.Citation1 It is important to eradicate transmission of not only wild polio viruses (WPVs) but also vaccine derived polioviruses. The elimination of WPVs using oral polio vaccine (OPV) was the first phase, and elimination of vaccine derived polioviruses using inactivated poliovirus vaccine (IPV) is the second phase.Citation2 This concept is endorsed by World Health Organization (WHO)Citation3 and India has already implemented the second phase i.e. elimination of vaccine derived polioviruses using IPV.
The poliomyelitis vaccine (inactivated) of Serum Institute of India Pvt. Ltd. Pune was licensed for manufacture and marketing by the National Regulatory Authority, India in February, 2011. It is indicated for active immunization of infants as young as 6 weeks of age, children and adults for the prevention of poliomyelitis caused by poliovirus types 1, 2, and 3.
Following licensure, we conducted a post marketing surveillance (PMS) study of IPV to further assess its safety on a larger population. The selection of subjects was governed by the permissible indications and contraindications of the vaccine as stated in the prescribing information and without limiting the eligibility criteria, as usually defined for early phase studies. The PMS phase of a vaccine ensures that the information is collected from a varied spectrum of subjects, thus yielding data that may not have been captured in pre-licensure studies. The outcome of such studies could be newer signals to the effects, pharmaco-epidemiological information, label changes with modified undesirable effects, indications and dosing schedules, and appropriate regulatory action.
Results
Study population
Study was conducted in children attending the immunization clinics or out-patient department of different hospitals in India. A total of 340 doctors including private practitioners from 17 states across India, participated in the study. Two thousand one hundred and twenty children received the vaccine as a part of their primary immunization series and 90 children received the vaccine as a booster dose. A total of 2210 doses of the vaccine were administered to children.
Baseline analysis
In all, 2210 children., 1258 (56.9%) male and 952 (43.1%) females participated in the study and all of them received a single dose of IPV. The IPV was administered in infants as a part of primary immunization either at 6, 10 and 14 weeks of age or in children as their scheduled booster dose at 15–18 months of age.
A total of 1531 (69.2%) children received the vaccine at 6 weeks, 378 (17.1%) received the vaccine at 10 weeks and 211 (9.5%) received at 14 weeks. Thus 2120 (96%) children received vaccine within primary immunization series and 90 (4.0%) children received booster dose at 15–18 months Concomitantly, DTwP-Hep-Hib (pentavalent) vaccine was administered to 1419 (64.2%) whereas DTwP-Hib vaccine was administered to 34 (1.53%) children. Along with IPV vaccination, OPV was also administered to all children following Expanded Programme on Immunization (EPI) and Indian Academy of Pediatrics (IAP) recommendation.
Safety
Post vaccination, the subjects were closely observed for 30 minutes at the immunization clinic to monitor and manage any immediate adverse events. Parents were informed to record the adverse events and any medication received by the subject, during the study period.
In total, there were 275 (12.44%) subjects who reported at least one or more solicited adverse event. Injection site pain 224 (10.14%), erythema 43 (1.95%), swelling 37 (1.67%) and fever 107 (4.84%) were the most commonly reported adverse events in this study (). Incidence of adverse events i.e., pain, swelling, fever and irritability were similar in male and female subjects (). However the difference in erythema observed in male (2.46%) and female (1.26%) subjects, was statistically significant (p-value = 0.0440), although has no clinical relevance.
Table 1. Cumulative safety overview after primary series & booster dose.
Table 2. Gender-wise safety overview.
Among the 2120 subjects for whom the safety data was available, 266 (12.55%) reported at least one solicited adverse event after primary series i.e 6, 10 or 14 weeks (). Injection site pain (10.28%), erythema (1.93%), swelling (1.70%) and fever (4.95%) were the frequently reported adverse events. Among the 90 subjects with assessable safety data, 9 (10%) reported at least one solicited reaction after booster dose at 15–18 months (). Injection site pain (6.67%), erythema (2.22%) and fever (2.22%) were the frequently reported adverse events.
Table 3. Safety overview after primary series cumulative safety analysis.
Table 4. Safety overview after booster dose safety analysis.
These adverse events were mild in intensity and resolved with or without concomitant medications such as analgesics and other supportive measures such as cold compresses at the injection site. No subject reported any unsolicited adverse reactions. No anaphylaxis, immediate allergic reaction or any case of serious adverse event (SAE) was observed or reported.
Discussion
As a part of Global Polio Endgame strategy, introduction of IPV in the immunization program is important. This vaccine will help to prevent re-emergence of polio by strengthening the immune system of children and providing double protection against polio.
The WHO states that globally all children should be fully vaccinated against polio. Every country should seek to achieve and maintain high levels of coverage with Poliomyelitis vaccine in support of the global commitment to eradicate polio.
Since April 2016, the Ministry of Health and Family Welfare, Government of India (GoI) has switched from trivalent to bivalent OPV. Now in India, only bOPV is being used in routine immunization as well as polio campaigns. To provide protection against type-2 poliovirus to naive children born post-switch, IPV would be the only source of providing type-2 immunity to children.
Inactivated Poliomyeltis Vaccine is considered very safe, whether given alone or in combination with other vaccines. Though local reactions are common with IPV use, they are generally mild and transient. There is no proven causal relationship to any adverse events other than minor local erythema (0.5–1%), induration (3–11%) and tenderness (14–29%).Citation4 No reports of anaphylaxis, thrombocytopenia or transverse myelitis after IPV have been published.Citation5
In a study conducted in India where in 590 children were accinated with IPV, no adverse events were reported, except local swelling less than 3 cm in 19 (3%) and redness less than 1 cm in 15 (3%) children. One child had local inflammation with fever (38°C). No deaths occurred during the 28 d follow up.Citation6 In the recently reported studies from China, IPV had a clinically acceptable safety profile in all studies. Grade 3 local and systemic reactions were uncommon. None of the SAEs were considered by the investigator as causally related to vaccination, and all had resolved by the end of the study.Citation7
The manufacturing and marketing authorization for Poliomyelitis Vaccine (Inactivated) was granted to Serum Institute of India Pvt Ltd. by the National Regulatory Authority (India), in February 2011. This study was conducted as a PMS study following the current regulatory guidelines applicable in India. The results obtained in this study after primary immunization series or booster dose were similar to the previous studies, published in literature.Citation4 Most of the adverse events were common and expected. The common local adverse events reported were injection site pain, swelling and erythema and the common systemic adverse event reported was fever. No neurological, hypersensitivity reactions or any other SAEs were reported in the study.
Apart from India, the IPV manufactured by Serum Institute of India Pvt. Ltd has been supplied in various regions like Middle East, South America, Africa and Asia. Thus, in total, from licensure in 2011 till March 2017, a total of 3.83 million doses have been distributed worldwide and no major safety concern has been reported so far.
The PMS studies wherein the data are collected from the field has its own set of limitations. Such studies sometimes have no control group and therefore the information gathered cannot be compared directly with the product already existing in the market, thereby making the interpretation of data difficult. A potential limitation of the study is that safety of this IPV vaccine was only assessed in a small cohort. Although, subjects from 17 states of India participated in this study, the data was not analyzed based on demography. Although, no comparator was used in the study and safety was assessed in a limited cohort, the data arising out of such studies cannot be ignored and is very much credible to justify its use on a larger sample population.
The present study has demonstrated an excellent safety/ tolerability profile of the Inactivated Poliomyelitis Vaccine of Serum institute of India Pvt. Ltd. This vaccine can be safely introduced in the routine childhood vaccination program of developed/ developing countries, so as to provide a better coverage.
Materials and methods
Study design
The current PMS study was conducted during December 2012- April 2015, at hospitals and immunization clinics across India to assess the safety of inactivated Poliomyelitis vaccine of Serum Institute of India Pvt. Ltd, Pune. This single arm study was conducted in infants aged 6–14 weeks and toddlers in their second year of life. Parents of the children were informed about the objective, study procedures, risk and the benefits. The study was performed in accordance with the Good Clinical Practice guidelines issued in ‘Schedule Y’ under Drugs and Cosmetic Act, Government of India.
Study objective
The objective of this study was to assess the safety and tolerability of inactivated Poliomyelitis vaccine of Serum Institute of India Pvt. Ltd., when administered to healthy Indian children either as a primary series dose or a booster dose.
Subjects and study procedures
The target population was infants aged 6–14 weeks attending the immunization clinics or hospitals for receiving their primary series of immunization or toddlers in their second year of life (15–18 months). The vaccine was administered in OPD/ immunization clinics. Information about the disease, common adverse events, study objective, study procedures, risk and benefits were explained by the study physician to the parents/ guardians before enrollment of their child in the study.
Dosage and administration
All participating children received at least one 0.5 ml single dose of the IPV vaccine, intramuscularly in the antero-lateral aspect of the thigh.
Poliomyelitis vaccine (Inactivated)
Composition of vaccine
Each 0.5 ml single human dose of the IPV of Serum Institute of India Pvt. Ltd., Pune contains poliomyelitis virus type 1, Mahoney strain 40 D antigen units, poliomyelitis virus type 2, MEF-I strain 8 D antigen units, poliomyelitis virus type 3, Saukett strain 32 D antigen units, 2-phenoxyethanol 2.5 mg and formaldehyde 12.5 mg as a preservative. A total of 39 different batches of the vaccine duly cleared by Central Drugs Laboratory, Kasauli were used in this PMS study. The vaccine was stored at 2–8°C and the cold chain for the vaccine was maintained at all the sites, throughout the study duration.
Assessment of reactogenicity (safety) and follow up
The vaccinees were observed for both local and systemic adverse events, including rare cases of anaphylaxis, if any. Reactogenicity was actively assessed by direct observation for 30 minutes post-vaccination at the clinic and later, observation by parents over the next 30 d. Parents were asked to observe and report any solicited and unsolicited adverse events to the Investigator, either in person or telephonically. Parents were asked to measure the rectal or axillary temperature using a digital thermometer, daily and in case of any local event, it was measured with a scale and recorded. Parents were also asked to report in case any medical attention was required during this period. The reported adverse events were transcribed on the Case Report Form by the study physician.
Assessment of severity of adverse reaction, relationship
Severity was assessed for pain, erythema, swelling and fever. Injection site pain was graded as minor reaction to touch (grade 1), cries or protests on touch (grade 2), cries when limb is moved/spontaneously painful (grade 3). For erythema and swelling longest diameter was noted in centimeter. For fever, highest temperature (axillary) recorded in a day was noted in degree Celsius (°C).
To assess the relationship of the adverse events to the study vaccine, causality assessment system was followed. Accordingly, Certain, Probable/ likely, Possible, Unlikely, Unrelated, Unassessable/ unclassifiable terminologies were used for categorization.Citation8The outcome of the event was categorized as recovered, ongoing at study conclusion, fatal (Death) and unknown.
Data analysis
Age was expressed as mean and the age distribution grouped by gender was expressed as number and percentage. Local and systemic adverse events were monitored and recorded after each dose of the vaccine. Frequency, percentage and exact binomial 95% CI was calculated. Intent to treat population was considered for reactogenicity analysis.
Disclosure of potential conflicts of interest
The authors HS, RD, SP and SS are employees of Serum Institute of India Pvt. Ltd.
Contribution of authors
The authors were responsible for the study design and contributed to implementation, monitoring, analysis and interpretation of the data.
Acknowledgments
The authors thank the children and their parents for participation in this study. The authors acknowledge the contributions of all doctors and para-medical staff who participated in the study including the support provided by the marketing division of Serum Institute of India Pvt. Ltd. during the conduct of the study. Special thanks to Bilthoven Biologicals, A Cyrus Poonawalla group based in Bilthoven, the Netherlands for providing Inactivated Poliomyelitis Vaccine bulk to Serum Institute of India Pvt Ltd. for formulation, filling and marketing. We also thank the biostatistician, Dr. Sanjeev Sarmukaddam for the statistical analysis of the data, emanating out of this study.
Funding
This study was financially supported by Serum Institute of India Pvt. Ltd., Pune.
References
- NCDC Newsletter, Quarterly Newsletter from the National Centre for Disease Control (NCDC). Jan-Mar 2014;3(1) [accessed 2017 Apr 28]. http://ncdc.gov.in/writereaddata/linkimages/NewsLtr0103_20146480274026.pdf
- John TJ. Will India need inactivated poliovirus vaccine (IPV) to complete polio eradication? Indian J Med Res. 2005;122:365–7. PMID:16456246
- Ending polio, one type at a time. Bull World Health Organ. 2012;90:482–3. PMID:22807591. [accessed 2017 Apr 28]. http://www.who.int/bulletin/volumes/90/7/BLT.12.020712.pdf?ua=1
- Nicholas C. Grassly. Immunogenicity and Effectiveness of Routine Immunization With 1 or 2 Doses of Inactivated Poliovirus Vaccine: Systematic Review and Meta-analysis. J Infect Dis. 2014;210:S439−46. doi:10.1093/infdis/jit601. PMID:24634499
- Weekly epidemiological record. Polio vaccines: WHO position paper: No. 9. January 2014;89:73–92. [accessed 2017 Apr 28]. http://www.who.int/wer/2014/wer8909.pdf
- Sutter RW, Kew OM, Cochi SL, Aylwar RB. In OW Plotkin SA, Vaccines, 2013, Chapter 28 − Poliovirus vaccine—live. 6th edition. Philadelphia: Elsevier-Saunders; 2013. pp. 573–597.
- Information sheet observed rate of vaccine reactions Polio vaccines. World Health Organization, May 2014. [accessed 2017 Apr 28] http://www.who.int/vaccine_safety/initiative/tools/polio_vaccine_rates_information_sheet.pdf
- The use of the WHO-UMC system for standardized case causality assessment. The Uppsala monitoring centre. [accessed 2017 Apr 28]. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf