Reproductive Toxicology Studies, Amendment No. 9, March, 18, 2005 - Adenovirus


IND -(b)(4)- 

Amendment No. 9

Sponsor:  Duramed Research Inc.

Product: Adenovirus types 4 and 7 (WI-38 cells) vaccine, 
live, oral tablets

Subject: Proposal for not conducting reproductive
toxicology studies

Date rec.: March, 18, 2005
Date rev.: April 11, 2005

From:  Marion F. Gruber, Ph.D., DVRPA

To:    Daryll L. Miller, DVRPA

Background:  Sponsor has an IND for Adenovirus vaccine live oral tablets type 4 and adenovirus vaccine live oral tablets type 7 for the prevention of acute respiratory disorder (ARD) associated with adenovirus infections in military recruit populations. 

Prior to the introduction of adenovirus vaccines in 1971, up to 80% of recruits developed adenovirus infections, 20% were hospitalized and a small number died.  Out of several virus serotypes, adenovirus types 4 and 7 accounted for the majority of hospitalized recruits.  Protective vaccines were administered beginning 1971 and used for Army, Navy, and Marine Corps recruits.  These vaccines markedly reduced adenovirus disease for basic training centers.  The sole producer of adenovirus vaccines (Wyeth Laboratories) ceased vaccine production in 1996.  All adenovirus vaccine stocks were depleted in 1999. Since then acute respiratory disease cases among Army trainees has been on the rise.  In 2001 Barr Laboratories signed a contract to produce adenovirus vaccines type 4 and 7.  The contract is administered by the US Army Medical Research and Materiel Command.

The previously adenovirus vaccine manufactured by Wyeth, was a live, oral vaccine.   The vaccine was administered to the military but not available for general use because of concerns about the live vaccine’s oncogenic potential and level of attenuation achieved in children.

During the May 10, 2004, pre-IND meeting between Duramed Research Inc. (formerly Barr Research Inc.) to discuss the clinical development plan for the investigational live oral adenovirus vaccines type 4 and 7 produced by Duramend, the issue of conducting reproductive toxicology studies was raised by FDA and documented in the meeting minutes. Duramed wishes to receive further input on the potential requirement for developmental toxicity studies with the investigational adenovirus vaccine and has presented a rationale for not conducting reproductive toxicology studies.

Sponsor’s rationale for not conducting reproductive toxicology studies:
1.Sponsor states that in exposed military populations, no clinically significant transfer of the vaccine virus strains to unvaccinated co-habitating recruit populations was observed (shedding). 
2.Sponsor states that the previously approved Wyeth vaccine has been used to vaccinate several million military recruits but that there appeared to be no available military records that identified reproductive toxicological or teratogenic adverse events.   Sponsor states that the majority of recruits vaccinated were men, however, women also received the Wyeth adenovirus vaccines “without any reported developmental abnormalities or other related events”  Note that the references cited in the amendment did not specifically address occurrences of developmental abnormalities probably due to the fact that the majority of volunteers enrolled in the studies were men.
3.Duramed will minimize the risks to female recruits by the following procedures: pregnancy test, ensure that the female military personnel is not pregnant prior to vaccine administration, female to agree to use effective contraception, females will be inoculated at the beginning of their 8 week training and will not be visited by spouses or significant others.
4.Duramed was unable to identify a validated biologically relevant animal model to evaluate live type 4 and 7 adenovirus vaccines. 
5.Duramed considers reproductive toxicology study neither feasible nor necessary.

Comments:  
1.The immune status of a pregnant individual is changed compared to nonpregnant subjects, thus, virus replication and dissemination in a pregnant subject may not be comparable to what is observed in healthy military male recruits.  However, the indication the sponsor is seeking for adenovirus vaccines types 4 and 7 is not for the general population, rather, it is restricted to military recruits.  Even though the percentage of female military recruits may have increased over the last 30 years, it would appear that it will be possible to administer the adenovirus vaccine under conditions that may be better controlled (e.g. protocol provisions and SOPs that exclude immunization of pregnant women) than if administered to the general population.
2.Sponsor states that the vaccine has no teratogenic potential.  However, no data or literature references were submitted (e.g. human pregnancy outcomes, data collected in pregnant women who received the previously licensed vaccine) to support this statement and to conclude that the vaccine would be safe when given to pregnant individuals. 
3. There is some data from published literature that suggests that adenovirus is a common viral pathogen identified in fetal samples from abnormal human pregnancies: Hideki Koi, et al 2001: "Differential expression of the Coxsackievirus and Adenovirus receptor regulates adenovirus infection of the placenta," Biology of Reproduction 64, 1001-1009, and Wenstrom KD et al, 1998 "Intrauterine viral infection at the time of second trimester genetic amniocentesis," Obstet. Gynecol. 92:420-424, and Van den Veyer et al, 1998, “Detection of intrauterine viral infection using PCR”, Mol. Genet. Metab., 63: 85-89.  Thus, some investigators believe that adenovirus infection is a previously unrecognized factor in adverse obstetric outcomes.  However, none of these papers report on the strains of adenovirus found in fetal tissue samples.  Other papers suggest that there is adenovirus of undetermined strains in fetal tissues, however, no fetal pathology was observed.  Therefore, whether adenovirus can be considered a pathogen that infects human placenta resulting in fetal abnormalities remains to be further investigated.
4.It appears that at present, information on pathogenesis and immunogenicity must be derived from human volunteer studies, as adenoviruses do not replicate in animal models.  Thus, there is no animal model that would lend itself to toxicity studies to evaluate the nonclinical safety of potential vaccine candidates, as the virus does not appear to replicate and/or induce an immune response in animal models.  There are some data by Pacini et al, 1984, J. Inf Disease; 150: 92-7 infecting cotton rats intra-nasally with adenovirus type 5 causing pulmonary disease similar to disease found in humans.  There were also attempts to infect rhesus monkeys with type 4 adenovirus but results were inconclusive and the conclusion was that rhesus monkeys are not readily susceptible to infection and would likely not serve as a useful model for vaccine testing. 

Thus, in the absence of an animal model able to elicit a pathological and immune response to the vaccine candidates, it is difficult to assess potential adverse effects on reproduction. In addition, reproductive toxicity studies in experimental models not conventionally used to assess the teratogenic potential of a product would make data interpretation difficult because of lack of historical control data.

Recommendation: Reproductive toxicology studies with adenovirus vaccines types 4 and 7 are currently not feasible due to lack of an animal model (i.e., strains do only replicate in human host).  Thus, performing these studies would very unlikely produce any useful data.  The safety of live adenovirus vaccines previously manufactured by Wyeth in pregnant individuals has not been established.  Evidence in the literature that infection of human pregnant subjects with wild-type adenovirus (unknown strain) leads to placental infection and adverse fetal outcomes needs further clarification/investigation.  The vaccine studied under IND 11813 should be contraindicated for use in pregnant women.  For the purpose of future licensure of the product, a pregnancy registry may be considered to capture and follow pregnant subjects (military recruits) that may have received the vaccine inadvertently.
