ADENOVIRUS SIDE EFFECTS

SIDE EFFECTS

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to the rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Multicenter Safety and Efficacy Trial

Safety of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral was evaluated in a multicenter, double-blind, randomized, placebo-controlled study that enrolled 3031 subjects who received vaccine and 1009 subjects who received placebo (lactose tablets). The study was conducted in healthy male (63%) and female (37%) active duty US Army and Navy military recruits during their basic training. The population had a mean age of 21 years, with an age range of 17 to 42 years. Race was 62% Caucasian, 18% African-American, 11% Hispanic, 3% Asian and 6% other. Subjects in both groups were administered other vaccines concomitantly with Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. The specific vaccines that each subject received varied and were dependent on their immunization history. The vaccines that were co-administered included Hepatitis A Vaccine, Inactivated (Merck & Co., Inc.), Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine (GlaxoSmithKline Biologicals), Hepatitis B Vaccine (Recombinant) (Merck & Co., Inc.), Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant (Merck & Co., Inc.), Influenza Vaccine, Live, Intranasal (MedImmune, LLC), Influenza Virus Vaccine (Sanofi Pasteur, Inc.), Measles, Mumps, and Rubella Virus Vaccine Live (Merck & Co., Inc.), Meningococcal (Groups A, C, Y and W-135) Polysaccharide, Diphtheria Toxoid Conjugate Vaccine (Sanofi Pasteur, Inc.), Meningococcal Polysaccharide Vaccine (Groups A, C, Y and W-135 Combined) (Sanofi Pasteur, Inc.), Poliovirus Vaccine Inactivated (Sanofi Pasteur, SA), Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Sanofi Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains live viruses that are shed in the stool and can cause disease if transmitted. Pasteur, Ltd.), Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (GlaxoSmithKline Biologicals), Typhoid Vi Polysaccharide Vaccine (Sanofi Pasteur, SA), Varicella Virus Vaccine Live (Merck & Co., Inc.), Yellow Fever Vaccine (Sanofi Pasteur, Inc.).

Serious Adverse Events

No deaths were reported during the multicenter safety and efficacy trial.

Serious adverse events in vaccine recipients included hematuria, gastroenteritis, febrile gastroenteritis, gastritis, pneumonia, and hematochezia.

Fifty-seven serious adverse events (SAEs) were reported during the six month study period with 39 reported between 0 and 56 days following treatment and 18 reported during the 56 to 180 day follow-up period. Thirtyfive subjects (1.2%) who received vaccine (25 between 0 and 56 days from the date of vaccination, 10 during the 56 to 180 day follow-up period) and 12 subjects (1.2%) who received placebo (9 between 0 and 56 days from the date of treatment, 3 during the 56 to 180 day follow-up period) experienced at least one SAE. The SAEs occurring between Day 0 and Day 56 post-vaccination in the vaccine group, possibly associated with the receipt of the vaccine product as determined by the investigator, were as follows: one subject with hematuria and gastroenteritis (at 9 days post vaccination), one subject with febrile gastroenteritis (at 4 days post vaccination, one subject with gastritis (at 23 days post vaccination), and one subject with pneumonia ( at 23 days post vaccination); one SAE (hematochezia) in the vaccine group occurred during the 56 to 180 day followup period and was determined to be possibly related to the vaccine product. A placebo recipient developed febrile acute respiratory disease where adenovirus Type 4 vaccine strain was detected from posterior pharyngeal and tonsillar swabbing and characterized by serotyping and polymerase chain reaction analysis.

Overall, the percentage of subjects who experienced at least one adverse event during the 56 day study period was 91.2% in the Adenovirus Type 4 and Type 7 Vaccine, Live, Oral group compared to 93.9% in the placebo group. No subject in either treatment arm discontinued the study due to an adverse event. Adverse reactions were captured on a 2-Week Daily Diary (for a minimum of the first 780 subjects) or a 1-Week Daily Diary (for all remaining subjects) and were also reported at each study visit up to Day 56 after vaccination. Any reported AEs for Days 0-14 for the safety cohort and for Days 0-7 for the remaining subjects were defined as “solicited” because they were almost exclusively recorded directly by the subject from a pre-defined diary checklist. Although pyrexia was defined as “solicited”, it was not on the pre-defined diary checklist. Any AEs reported spontaneously as part of the regular study visit or during a spontaneous visit to the clinic, for Days 15-56 for the safety cohort and Days 8-56 for the remaining subjects were designated as “non-solicited”.

Solicited Adverse Reactions

The following solicited adverse reactions were collected through daily diaries: stuffy nose, cough, sore throat, stomach pain, headache, diarrhea, nausea, and joint pain (within 14 days post enrollment for subjects in the initial safety cohort (n=878) and within 7 days post enrollment all subjects (n= 4040) for the rest of safety population). Those solicited adverse reactions reported by ≥ 5 % of subjects in either the vaccine or placebo treatment groups are presented in Table 1.

Table 1: Solicited Adverse Reactions, Days 0-7 for All Subjects and Days 8-14 for the Safety Cohort, Reported by ≥ 5% of Subjects in the Multicenter Safety and Efficacy Trial

Pyrexia (temp ≥ 100.5°F) within 7 days, was reported to occur in 1.4% (42/3030) of vaccine recipients and 0.5% (5/961) of placebo recipients who were not diagnosed with ARD. During the 8-14 days post vaccination, rates of pyrexia were 0.6% (4/659) and 1.1% (2/170) in vaccine and placebo recipients respectively.

Non-Solicited Adverse Reactions

Non-solicited adverse reactions, that occurred Days 15-56 in the safety cohort and Days 8-56 for all remaining subjects, reported by ≥ 5 % of subjects in either the vaccine or placebo treatment groups are presented in Table 2.

Table 2: Nonsolicited Adverse Reactions, Days 15-56 for the Safety Cohort and Days 8-56 for all Remaining Subjects, Reported by ≥ 5% of Subjects in the Multicenter Safety and Efficacy Trial

Less common (less than 5%) adverse reactions reported in the clinical trial in military recruits receiving Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, versus placebo, respectively included rhinorrhea (128 [4.22%] vs. 25 [2.48%]), pain in extremity (130 [4.29%] vs. 37 [3.67%]), and pyrexia (fever greater than or equal to100.5 °F) (126 [4.16%] vs. 49 [4.86%]).

Safety and Immunogenicity Trial

Five SAEs were reported among the 58 subjects in the safety and immunogenicity trial. Two SAEs occurred among the vaccine recipients: one case of pneumonia reported on Day 33 of the follow-up period, and a report of appendicitis occurring on Day 118 of follow-up period. Three SAEs were reported among placebo recipients: one case of pneumonia on Day 10 and one case of upper respiratory infection reported on Day 14, and a right thigh abscess reported at Day 91.