Safety and immunogenicity of an indigenously developed Haemophilus influenzae type b conjugate vaccine through various phases of clinical trials (original) (raw)

Abstract

Hib is estimated to cause at least 3 million cases of serious disease every year as well as approximately 386,000 deaths. 2 The burden of Hib disease is proved in large studies conducted in Africa, Asia and Latin America where the vaccine was found to be useful in reducing childhood infections. 3-5 In view of demonstrated safety and efficacy, World Health Organization (WHO) recommends that conjugate Hib vaccines should be included in all routine infant immunization program. 2 Hib vaccination also reduces nasopharyngeal colonization with the organism, leading to substantial reduction in disease incidence than can be directly attributed to the effects of the vaccine. This indirect effect (herd immunity) has been amply demonstrated in several post-introduction efficacy studies in which near-elimination of Hib disease occurred even when vaccine coverage was sub-optimal. 2,6-8 The successful reduction of Hib disease including pneumonia and meningitis has been observed in Hib vaccine recipients in developing countries like Gambia, Uganda, Kenya and Bangladesh. 9-12 In these countries, the Hib conjugate vaccine was made available from vaccine manufacturers and/or global organizations aiming at improved immunization services. The actual number of children receiving a third dose of the vaccine globally has increased from 8% of the world's surviving infants in 1999 to 22% in 2006. 13 The epidemiology of Hib infections in India has revealed that the infection is prevalent, even in India. Hib is a leading cause of bacterial childhood meningitis and important cause of severe pneumonia, in India. Approximately, 19% (410,000) of under 5 deaths in India are due to pneumonia. 14 India accounts for almost 40% of worldwide childhood pneumonia cases. However, experts opine that these estimates are underestimated. The case-fatality rate for Hib meningitis was 11% overall, in a study conducted in India. 15 A study showed that about 30% of Indian children who survived Hib meningitis, suffered from major disabilities. 16 There is an increase in consensus among experts that estimates of Hib pneumonia rates in India are underestimated. A large percent of Indian children are thought to be at a high risk due to increasing resistance to antibiotics as well as to limited access to health care facilities. As per hospital data, 30-45% cases of meningitis and 8-12% cases of pneumonitis in India are due to Hib. It is estimated that annual incidence of Hib In view of the need for a cost effective Haemophilus influenzae type b (Hib) conjugate vaccine, a lyophilized vaccine as capsular polysaccharide (PRP) conjugated to tetanus toxoid (Sii HibPRO) was indigenously developed by Serum Institute of India Ltd., Pune (SIIL). From 2004-07, this new vaccine underwent a series of clinical studies before its licensure by National Regulatory Authority (NRA). This paper discusses the results obtained during the clinical development of this vaccine. On finding the vaccine to be safe in animal toxicity studies, a Phase I single dose study was carried out to assess the safety profile of Sii HibPRO in healthy adult male volunteers. Subsequently, in Phase III pre-licensure study, immunogenicity and safety of Sii HibPRO was assessed and compared with Hib tetanus conjugate vaccine (Act-HIB) of Aventis, France. Immunogenicity was evaluated based upon serum anti-PRP IgG antibody concentrations by ELISA at prevaccination and one month each after the second and third dose. Safety was evaluated by recording details of adverse events after each dose of the vaccine. Postvaccination after the third dose, there was 100% seroprotection (anti PRP IgG titre ≥ 0.15 μg/ml) in both the groups. Long term protection (≥1 μg/ml) was achieved in 95.2% and 98.06% infants in Sii HibPRO and Act-HIB groups, respectively. At 15 months, prior to booster dose, 30 children in each group were evaluated and all were found to be seroprotected. Post booster, all of them responded with a strong boost response. Safety of Sii HibPRO was re-established in the post marketing surveillance in which 2,739 doses were administered to 1,029 infants, in 23 cities across India.

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