Each novel vaccine candidate needs to be evaluated for safety, immunogenicity, and protective efficacy in humans before it is licensed for use. After initial safety evaluation in healthy adults, each vaccine candidate follows a unique development path. This article on clinical development gives an overview on the development path based on the expectations of various guidelines issued by the World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (USFDA). The manuscript describes the objectives, study populations, study designs, study site, and outcome(s) of each phase (Phase I-III) of a clinical trial. Examples from the clinical development of a malaria vaccine candidate, a rotavirus vaccine, and two vaccines approved for human papillomavirus (HPV) have also been discussed. The article also tabulates relevant guidelines, which can be referred to while drafting the development path of a novel vaccine candidate.

BackgroundAcute liver failure (ALF) is marked by a sudden loss of hepatic function and is associated with a high mortality rate in children. The etiology of ALF is shown to vary geographically. This study assessed the frequency of hepatotropic viruses as etiological agents of ALF in Indian children.MethodsThis retrospective study enrolled children aged 0–18 years with confirmed ALF admitted to Christian Medical College, Vellore and King Edward Memorial Hospital and Research Center, Pune between January 2003 and December 2005. The frequency of hepatotropic viruses as etiological agents in children with ALF aged ≤18 years was calculated with 95 % confidence interval (CI). Descriptive analyses of demographic characteristics, clinical signs and symptoms of ALF, choice of treatment and outcomes were performed.ResultsOf 76 children enrolled, 54 were included in the per-protocol analyses. Mean age of children with ALF was 5.43 years (standard deviation = 3.62); 51.9 % (28/54) were female. The percentage of children positive for anti-hepatitis A virus (HAV) IgM and hepatitis B surface antigen was 65.9 % (27/41; 95 % CI 49.4–79.9) and 15.9 % (7/44; 95 % CI 6.6–30.1), respectively. The final cause of ALF was HAV (36.3 %) followed by hepatitis B virus (HBV; 8.8 %). Before and during admission, encephalopathy was observed in 77.8 % (42/54) and 63.0 % (34/54) of children, respectively. A high number of children (46/54; 85.2 %) required intensive care and ALF was fatal in 24.1 % (13/54). The proportion of deaths due to HAV and HBV was 18.5 % (5/27) and 57.1 % (4/7), respectively.ConclusionsHAV and HBV were the most common etiological agents of ALF in Indian children. Primary prevention by vaccination against HAV and HBV in young children may be useful in the prevention of ALF due to viral hepatitis in India.

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BackgroundCervical cancer ranks second among all cancers reported in Sri Lankan women. This study assessed the prevalence and type-distribution of human papillomavirus (HPV) among Sri Lankan women with invasive cervical cancer (ICC) and pre-cancerous lesions.Methods114 women aged 21 years and above, hospitalized in the National Cancer Institute, Sri Lanka with a diagnosis of ICC or cervical intraepithelial neoplasia (CIN) 2/3 were prospectively enrolled between October 2009 and September 2010 (110430/NCT01221987). The cervical biopsy or excision specimens collected during routine clinical procedures were subjected to histopathological review. DNA was extracted from samples with a confirmed histological diagnosis and was amplified using polymerase chain reaction and HPV DNA was detected using Enzyme Immuno Assay. HPV positive samples were typed using reverse hybridization Line Probe Assay.ResultsOf the cervical samples collected, 93.0% (106/114) had a histologically confirmed diagnosis of either ICC (98/106) or CIN 2/3 (8/106). Among all ICC cases, squamous cell carcinoma was diagnosed in the majority of women (81.6% [80/98]). HPV prevalence among ICC cases was 84.7% (83/98). The HPV types most commonly detected in ICC cases with single HPV infection (98.8% [82/83]) were HPV-16 (67.3%) and HPV-18 (9.2%). Infection with multiple HPV types was recorded in a single case (co-infection of HPV-16 and HPV-59).ConclusionsHPV was prevalent in most women with ICC in Sri Lanka; HPV-16 and HPV-18 were the predominantly detected HPV types. An effective prophylactic vaccine against the most prevalent HPV types may help to reduce the burden of ICC disease.

In this phase III, open-label, multicenter, and descriptive study in India, children primed with 3 doses (at ages 6, 10, and 14 weeks) of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were randomized (1:1) to receive a booster dose at 9 to 12 (early booster) or 15 to 18 months old (late booster) in order to evaluate impact of age at booster. We also evaluated a 2-dose catch-up vaccination plus an experimental booster dose in unprimed children age 12 to 18 months. The early booster, late booster, and catch-up vaccinations were administered to 74, 95, and 87 children, respectively; 66, 71, and 81 children, respectively, were included in the immunogenicity according-to-protocol cohort. One month postbooster, for each PHiD-CV serotype, >95.2% (early booster) and >93.8% (late booster) of the children had antibody concentrations of >0.2 g/ml; >96.7% and >93.0%, respectively, had opsonophagocytic activity (OPA) titers of >8. The postbooster antibody geometric mean concentrations (GMCs) were in similar ranges for early and late boosters; the OPA titers appeared to be lower for most PHiD-CV serotypes (except 6B and 19F) after the early booster. After dose 2 and postbooster, for each PHiD-CV serotype, >88.6% and >96.3%, respectively, of the catch-up immunogenicity according-to-protocol cohort had antibody concentrations of >0.2 g/ml; >71.4% and >90.6%, respectively, had OPA titers of >8. At least 1 serious adverse event was reported by 2 children in the early booster (skin infection and gastroenteritis) and 1 child in the catch-up group (febrile convulsion and urinary tract infection); all were resolved, and none were considered by the investigators to be vaccine re- Streptococcus pneumoniae is the leading cause of pneumonia, meningitis, and septicemia. Worldwide, pneumococcal infections are estimated to have been responsible for 541,000 deaths in 2008 in children Ͻ5 years of age, with a high burden in Southeast Asia (108,000 deaths in 2008 in children Ͻ5 years) (http://www.who.int/ immunization/monitoring_surveillance/burden/estimates/Pneumo _hib/en/).The 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) has been shown to be immunogenic and well tolerated in infants in India (1). Moreover, recent double-blind randomized controlled trials demonstrated that infant vaccination with PHiD-CV was effective in preventing vaccine-type invasive pneumococcal disease (2, 3), communityacquired pneumonia (4, 5), and acute otitis media (6).PHiD-CV is typically given as a 2-or 3-dose primary series in infants, with a booster dose administered in their second year of life. However, in some countries, vaccination visits beyond the first year are not routine; thus, vaccination ends at the age of Յ6 months, without a booster dose being administered. Developing countries generally opt for a 3-dose primary schedule for PHiD-CV, without a booster dose. Moreover, compliance with vaccination decreases as children get older (7). Nevertheless, epi...