Toxicology Review - Adenovirus

BLA: 125296

IND: --(b)(4)--

Sponsor: Duramed Research Inc.

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

Proposed use: Immunization of military population in which epidemic respiratory disease due to adenovirus, types 4 and 7, has been shown likely to occur.

Reviewer: Claudia Wrzesinski

Précis: Although no formal toxicology studies were performed for this product, a review of the literature suggests risks for use in pregnant women. The company has proposed a pregnancy category C. However, due to possible risk, a pregnancy category D is more appropriate. Approved vaccines with pregnancy category D already include BioThrax and ACAM2000.

Introduction: Adenovirus types 4 and 7 vaccine (WI-38 cells)  is a live vaccine for the prevention of acute respiratory disorder (ARD) and pneumonia associated with adenovirus infections in military recruit populations.  Before vaccines were available in 1971, up to 80% of recruits developed adenovirus infections and the virus was consistently isolated in 30-70% of trainees with ARD.  In addition, adenoviruses were associated with 90% of the cases of pneumonia among trainees.  The vaccine significantly reduced the adenovirus disease for basic training centers.  In 1996 Wyeth stopped the vaccine production and all stocks were depleted in 1999.  In 2001 Barr Laboratories renewed the process of manufacturing adenovirus vaccines type 4 and 7. 

It has been shown that the coxsackievirus and adenovirus receptor (CAR) is expressed on the placenta.  Binding of the adenovirus on the CAR receptor may enable vertical transmission of the virus and induce placental dysfunction resulting in complications including spontaneous miscarriage, preeclampsia, fetal growth restriction and preterm labor1 . 

Toxicology Study Review: No specific toxicology studies were conducted for this vaccine since there is no validated biological relevant animal model known for the evaluation of live type 4 and 7 adenovirus vaccine.  By performing a thorough literature search, several studies which raise concern for the use of a live adenoviral vaccine in pregnant women were identified (see attached review of IND --(b)(4)--.

The intrauterine infection with adenoviruses has been associated with the development of nonimmune hydrops in several studies.  In a study conducted 1998, investigators Van den Veyver and colleagues collected from 303 women sample material including amniotic fluid and fetal specimen like blood, pleural effusion, fetal ascites and tissue samples. These samples were tested by PCR for adenovirus, enterovirus, parvovirus, cytomegalovirus (CMV), herpes simplex virus, Epstein-Barr virus (EBV) and respiratory syncytial virus (RSV).  In these experiments the authors found a strong association of nonimmunogen hydrops with a high incidence of viral infection, especially adenoviral infection.  The adenovirus was also frequently amplified from ascites, pleural infusion, miscellaneous tissues (i.e., myocardium) and several adenovirus infected fetuses displayed intrauterine growth restriction2. 

Two case-reposts show an association of hydrops fetalis in combination with heart problems and adenovirus infection of the fetus.  In the first case report, a stillborn 31 week old fetus was diagnosed with hydrops, cardiomegaly, and aortic valve stenosis.  PCR from the myocardial and aortic valve tissue was performed. Both tissues tested positive for adenovirus, but not for enterovirus, CMV, herpes simplex virus, parvovirus, EBV and RSV 3. 

The second case report described a 27 week old fetus with hydrops fetalis associated with fetal tachyarrhythmia who in the following was preterm delivered at week 29.  PCR of the amniotic fluid showed positive results for adenovirus, but not for parvovirus, herpes simplex virus, CMV, enterovirus and RSV4. 

In a study by Baschat and colleagues 1090 women underwent detailed prenatal ultrasound examination and amniocentesis where an aliquot of amniotic fluid was collected.  Multiplex viral PCR was performed in the amniotic fluid sample.  The authors found that the incidence of neural tube defects and echogenic liver foci was significantly higher in patients with a positive PCR for adenovirus than in the group that tested negative for adenovirus5. 

These findings are summarized in “Fields Virology” which states that the presence of adenovirus in amniotic fluid is frequently associated with abnormal fetuses6, and specifically cites the above mentioned study by Baschat and colleagues.

Additionally adenoviruses account for 3-5% of infectious disease in children under 5 years old, leading to rhinitis, pharyngitis, tracheitis, gastroenteritis or keratoconjunctivitis. In neonates disseminated adenovirus infections can occur and result in a fatal outcome7.

Assessment: These studies raise significant concerns regarding toxicities of adenoviruses for pregnancies. Therefore in accordance with the CFR (201.57(4)) the label for this product should be “pregnancy category D” for the “Adenovirus types 4 and 7 Vaccines, Live, Oral.” The sponsor has proposed a category C labeling for pregnancy which would be appropriate if indications of potential harm for humans were not evident from the scientific literature. The concern for the potential human reproductive and developmental risk was communicated to the company by fax on May 3, 2005 (see attached fax).

Conclusions: In accordance with the CFR the label “pregnancy category D” should be used for the “Adenovirus types 4 and 7 (WI-38 cells) vaccine.”

Communications: The wording in the label should read as followed:  

“WARNINGS AND PRECAUTIONS:


Adenovirus may be associated with fetal harm when administered to a pregnant woman.  Pregnant women should not get vaccinated with Adenovirus Type 4 and Type 7 Vaccines, Live, Oral unless the potential benefits of vaccination have been determined to outweigh the potential risk to the fetus.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to a fetus. (5.3)

5.3 Pregnancy 
Pregnancy Category D: 
Adenovirus Type 4 and Type 7 Vaccines, Live, Oral can cause fetal harm when administered to pregnant women. Based on case reports of disseminated adenovirus infection in premature and severely ill infants, as well as epidemiologic studies in pregnant women in which evidence of adenovirus infection was detected in amniotic fluid in association with fetal malformation and pregnancy abnormalities, Adenovirus Type 4 and Type 7 Vaccines, Live, Oral may cause fetal harm when administered to a pregnant woman1-5.  If this product is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.   Use in Specific Populations
8.1 Pregnancy

Pregnancy Category D.
There are no animal reproduction studies and no adequate and well-controlled clinical studies of Adenovirus Type 4 and Type 7 Vaccines, Live, Oral in pregnant women.  Based on case reports of disseminated adenovirus infection in premature and severely ill infants, as well as epidemiologic studies in pregnant women in which evidence of adenovirus infection was detected in amniotic fluid in association with fetal malformation and pregnancy abnormalities, Adenovirus Type 4 and Type 7 Vaccines, Live, Oral may cause fetal harm when administered to a pregnant woman.  If this product is used during pregnancy, or if the patient becomes pregnant within 6 weeks of taking Adenovirus Type 4 and Type 7 Vaccines, Live, Oral, the patient should be apprised of the potential harm to the fetus.  Women of childbearing potential should be advised to use an effective method of contraception while receiving Adenovirus Type 4 and Type 7 Vaccines, Live, Oral and for up to 6 weeks afterwards.

Five pregnancies were reported among women enrolled in the Phase 3 study of Adenovirus Type 4 and Type 7 Vaccines, Live, Oral.  Four of the subjects were estimated to have conceived 2 to 13 days prior to vaccination.  One subject 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.

All cases in which a women received Adenovirus Type 4 and Type 7 Vaccines, Live, Oral during pregnancy or becomes pregnant (conception occurs) within 6 weeks following vaccination should be reported to the Adenovirus Pregnancy Registry by calling XXX-XXX-XXXX.

Reference:
1.Van den Veyver et al. 1998. Detection of intrauterine viral infection using the polymerase chain reaction. Mol Genet Metab, 63: 85-95
2.Calvin et al. 2000. Fatal intrauterine adenoviral endomyocarditis with aortic and pulmonary valve stenosis: diagnosis by polymerase chain reaction. Hum Pathol. 31(11):1433-5
3.Ranucci-Weiss et al. 1998. Intrauterine adenoviral infection associated with fetal non-immune hydrops. Prenat.  Diagn. 18(2):182-5
4.Baschat et al., 2003 Is adenovirus a fetal pathogen? Am J Obstet Gynecol. 189(3):758-63.
5.Fields Virology, fifth edition, 2007, p2409

17.3     Pregnancy
Women should be informed that if they are or suspect being pregnant, they should inform their healthcare provider before receiving the vaccine. 

Women should be informed to avoid becoming pregnant following vaccination to prevent the fetus from being exposed to virus during the period of fecal shedding. 

If a pregnant woman receives Adenovirus Type 4 and Type 7 Vaccines, Live, Oral or a women becomes pregnant within the 6 weeks following administration of vaccination, they should be enrolled in the Adenovirus Pregnancy Registry.  [See Pregnancy (8.1].”

Concurrence: Dr. Green


Footnotes



1 Koi et al., Biol Reprod., 2001; Arechavaleta-Velasco, J Reprod Immunol., 2002


2 Van den Veyver et al., Mol Genet Metab, 1998


3 Calvin et al., Hum Pathol., 2000


4 Ranucci-Weiss et al., Prenat.  Diagn., 1998


5 Baschat et al., Am J Obstet Gynecol, 2003


6 Fields Virology, fifth edition, 2007, p2409


7 Rieger-Fackeldey, Infection, 2000
