Vaccine Information: Adenovirus Type 4 and Type 7 Vaccine, Live (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Immune System Disorders: Hypersensitivity reactions (including anaphylaxis)

Nervous System Disorders: Guillain-Barré syndrome

7 DRUG INTERACTIONS

7.1 Concomitant Vaccine Administration

In clinical studies Adenovirus Type 4 and Type 7 Vaccine, Live, Oral was administered concurrently with other vaccines [See Adverse Reactions (6.1)]. Data were not available to assess whether Adenovirus Type 4 and Type 7 Vaccine, Live, Oral interferes with the immune response to the other vaccines.

7.2 Immunosuppressive Therapies

There are no data regarding the use of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral concomitantly with immunosuppressive therapies, e.g., irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) [See Warnings and Precautions: Altered Immunocompetence (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Do not administer Adenovirus Type 4 and Type 7 Vaccine, Live, Oral to pregnant females [See Contraindications (4.1)]. It is not known whether Adenovirus Type 4 and Type 7 Vaccine, Live, Oral can cause fetal harm when administered to a pregnant woman. Naturally occurring infection with adenoviruses has been associated with fetal harm.

Pregnancy should be avoided for 6 weeks following receipt of vaccine.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Labor and Delivery

There is no information regarding the effect of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral on labor and delivery. Fecal shedding during delivery may result in vaccine virus transmission to the newborn infant.

Data

Human Data

Five pregnancies were reported among women enrolled in the multicenter safety and efficacy trial of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. Four of the subjects (3 vaccine recipients and 1 placebo recipient) were estimated to have conceived 2 to 13 days prior to vaccination. One subject (vaccine recipient) conceived approximately 21 weeks after vaccination. The deliveries to all five of the subjects were of healthy infants at estimated gestational ages between 36 and 40 weeks.

8.2 Lactation

Risk Summary

There are no data on the presence of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral in human milk, effects on milk production, or on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Adenovirus Type 4 and Type 7 Vaccine, Live, Oral and any potential adverse effects on the breastfed infant from Adenovirus Type 4 and Type 7 Vaccine, Live, Oral or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is contraindicated for use in pregnant women [See Pregnancy (4.1)]. Females of reproductive potential should have a pregnancy test prior to treatment with Adenovirus Type 4 and Type 7 Vaccine, Live, Oral.

Contraception

Advise females of reproductive potential to use effective contraception during treatment with Adenovirus Type 4 and Type 7 Vaccine, Live, Oral and for 6 weeks following receipt of vaccine.

8.4 Pediatric Use

The safety and effectiveness of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral has not been evaluated in the age groups from birth through age 16.

8.5 Geriatric Use

Clinical studies of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. There are no data to support use of this vaccine in geriatric (person ≥ 65 years) populations.

11 DESCRIPTION

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains viable, selected strains of human adenovirus Type 4 and human adenovirus Type 7 prepared in human-diploid fibroblast cell cultures (strain WI-38). The virus strains have not been attenuated. The cells are grown and the virus growth maintained in Dulbecco’s Modified Eagle’s Medium, fetal bovine serum, and sodium bicarbonate. The virus is harvested, freed of particulate cellular material by filtration, formulated and dried by lyophilization. The dried virus material includes monosodium glutamate, sucrose, D-mannose, D-fructose, dextrose, human serum albumin, potassium phosphate, and plasdone C.

The final vaccine is composed of two tablets (one tablet of Adenovirus Type 4 and one tablet of Adenovirus Type 7) designed to pass intact through the stomach and release the live virus in the intestine. Each enteric-coated tablet contains an inner core tablet containing anhydrous lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate, and live adenovirus, either Type 4 or Type 7, at a potency of no fewer than 32,000 tissue-culture infective doses (4.5 log10 TCID50 ) per tablet. The outer tablet layer contains microcrystalline cellulose, magnesium stearate, and anhydrous lactose, with an enteric coating consisting of cellulose acetate phthalate, alcohol, acetone, and castor oil. The Type 7 tablet also contains FD&C Yellow #6 aluminum lake dye.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is a live oral vaccine that replicates in the intestinal tract and induces immunity in persons with low or no pre-existing neutralizing antibodies.

12.2 Pharmacodynamics

Vaccine Virus Shedding

Fecal shedding of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral strain viruses was evaluated in a safety and immunogenicity study of 58 subjects (30 vaccine recipients and 28 placebo recipients) [See Clinical Studies (14)]. Stool or rectal swabs and throat swabs were collected on Day 0, 7, 14, 21, 28 and 56. Vaccine virus strains were shed in the stool as early as day 7 following vaccination. Eight of 30 vaccine recipients (27%) tested positive at least once for Adenovirus Type 4 fecal shedding; 18 of 30 vaccine recipients (60%) tested positive for Adenovirus Type 7 fecal shedding. No adenovirus shedding was detectable in any subject by 28 days following vaccination. Vaccine strain virus was not detected in the throat of any subject.

13 NONCLINICAL PHARMACOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility.

14 CLINICAL STUDIES

14.1 Multicenter Safety and Efficacy Trial

A multicenter, double-blind, randomized, placebo-controlled study in US military recruits evaluated the safety and efficacy of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral to prevent wild Type 4 adenovirus-associated febrile acute respiratory disease (ARD) and to induce neutralizing antibody to Type 7 adenovirus. A seroconversion endpoint rather than prevention of clinical disease was used to assess efficacy of the Type 7 adenovirus vaccine component of this product as the incidence of febrile ARD due to Type 7 adenovirus was not anticipated to be high enough to permit a meaningful statistical assessment of the clinical effect of this vaccine component. Subjects were randomized to either the vaccine group or the placebo group in a 3:1 ratio. 4041 subjects were randomized, and 4040 subjects were analyzed. Females and males aged 17 or older and in good physical health were included in the study. No subjects were immunosuppressed or being treated with systemic immunosuppressive therapy. Baseline serology data is presented in Table 3.

Table 3: Baseline Serology in Multicenter Safety and Efficacy Trial

Vaccine

N=3031

Placebo

N=1009

Total

N=4040

Type 4 Titer

n (%)

n (%)

n (%)

Negative*

1906 (63%)

678 (67%)

2584 (64%)

Positive**

1123 (37%)

331 (33%)

1454 (36%)

Type 7 Titer

Negative*

1159 (38%)

377 (37%)

1536 (38%)

Positive**

1870 (62%)

632 (63%)

2502 (62%)

* Titer value was <1:4 at visit 0.

** Titer value was ≥1:4 at visit 0.

Adenovirus Type 4 Efficacy and Immunogenicity

Febrile Acute Respiratory Disease (ARD): The results for the primary analysis of vaccine efficacy (VE) for adenovirus Type 4 and rate of wild Type 4 febrile ARD, are summarized in Table 4. Cases were defined as subjects with one or more clinical signs and symptoms of ARD (mild to severe: sore throat, cough, rhinorrhea, nasal congestion, rales or rhonchi), an oral temperature > 100.5°F, and throat culture positive for wild Type 4 adenovirus infection. Vaccine type Adenovirus was distinguished from wild type by a Polymerase Chain Reaction (PCR) assay.

Table 4: Wild Adenovirus Type 4 Febrile ARD Cases (Day 0-56) In the Multicenter Safety and Efficacy Trial

Adeno Type 4 ARD case

Statistic

Vaccine

N=3031

Placebo

N=1009

Yes

n

1*

48

VE (95% CI)§

99.3% (96.0%, 99.9%)

*one additional subject met the case definition but had non-vaccine serotype (B3) adenovirus

§Vaccine efficacy (VE) defined as: VE = 1 — RR, where RR = P(vaccine)/P(placebo) was the relative risk of ARD attack in subjects who received vaccine compared to placebo; 2-sided confidence interval, by using exact statistical methods.

Seroconversion Rate: Adenovirus Type 4 seroconversion rate is presented in Table 5. Seroconversion is defined as the development of a Type 4 neutralizing antibody titer of greater or equal to 1:8 at Day 26 after vaccination in subjects whose baseline titer was less than 1:4.

Table 5: Adenovirus Type 4 Seroconversion Rate (Day 26) in the Multicenter Safety and Efficacy Study

Adenovirus Type 4 and Type 7 Vaccine, Live Oral

Placebo

N

Seroconversion

N

Seroconversion

n

%

(95% CI)

n

%

(95% CI)

1841

1739

94.5%

( 93.4%, 95.5% )

653

69

10.6 %

( 8.2%, 12.9% )

Adenovirus Type 7 Immunogenicity

Febrile Acute Respiratory Disease: No Type 7 adenovirus-associated febrile or afebrile ARD cases were reported for either placebo or vaccine groups. This was expected given the estimated attack rate of adenovirus Type 7 in the military base training setting at the time of the study. Seroconversion was the primary evaluation of Type 7 effectiveness.

Seroconversion Rate: Results for the primary analysis of adenovirus Type 7 efficacy, seroconversion rate at Day 26, are summarized in Table 6. Seroconversion is defined as the development of a Type 7 neutralizing antibody titer of greater or equal to 1:8 at Day 26 after vaccination in subjects whose baseline titer was less than 1:4.

Table 6: Adenovirus Type 7 Seroconversion Rate (Day 26)

Adenovirus Type 4 and Type 7 Vaccine, Live Oral

Placebo

N

Seroconversion

N

Seroconversion

n

%

(95% CI)

n

%

(95% CI)

1120

1051

93.8%

(92.4%, 95.2% )

359

19

5.3%

(3.0%, 7.6% )

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