An adenovirus previously isolated from a mesenteric lymph node from a chimpanzee was fully sequenced and found to be similar in overall structure to human adenoviruses. The genome of this virus, called C68, is 36,521 bp in length and is most similar to subgroup E of human adenovirus, with 90% identity in most adenovirus type 4 open reading frames that have been sequenced. Substantial differences in the hexon hypervariable regions were noted between C68 and other known adenoviruses, including adenovirus type 4. Neutralizing antibodies to C68 were highly prevalent in sera from a population of chimpanzees, while sera from humans and rhesus monkeys failed to neutralize C68. Furthermore, infection with C68 was not neutralized from sera of mice immunized with human adenovirus serotypes 2, 4, 5, 7, and 12. A replication-defective version of C68 was created by replacing the E1a and E1b genes with a minigene cassette; this vector was efficiently transcomplemented by the E1 region of human adenovirus type 5. C68 vector transduced a number of human and murine cell lines. This nonhuman adenoviral vector is sufficiently similar to human serotypes to allow growth in 293 cells and transduction of cells expressing the coxsackievirus and adenovirus receptor. As it is dissimilar in regions such as the hexon hypervariable domains, C68 vector avoids significant cross-neutralization by sera directed against human serotypes.

Replication-Defective Vector Based on a Chimpanzee Adenovirus

As a major cause of acute and chronic liver disease as well as hepatocellular carcinoma, hepatitis B virus (HBV) continues to pose significant health problems world-wide. Recombinant hepatitis B vaccines based on adenovirus vectors have been developed to address global needs for effective control of hepatitis B infection. Although considerable progress has been made in the construction of recombinant adenoviruses that express large amounts of HBV gene products, preclinical immunogenicity and efficacy testing of candidate vaccines has remained difficult due to the lack of a suitable animal model. We demonstrate here that chimpanzees are susceptible to enteric infection by human adenoviruses type 7 (Ad7) and type 4 (Ad4) following oral administration of live virus. Moreover, after sequential oral immunization with Ad7- and Ad4-vectored vaccines containing the hepatitis B surface antigen (HBsAg) gene, significant antibody responses to HBsAg (anti-HBs) were induced in two chimpanzees. After challenge with heterologous HBV, one chimpanzee was protected from acute hepatitis and the other chimpanzee experienced modified HBV-induced disease. These data demonstrate the feasibility of using orally administered recombinant adenoviruses as a general approach to vaccination.

Immunogenicity and efficacy testing in chimpanzees of an oral hepatitis B vaccine based on live recombinant adenovirus

Cercopithecine herpesvirus 1 (B virus), enzootic among monkeys of the genus Macaca, causes minimal morbidity in its natural host. In contrast, human B-virus infection presents as rapidly ascending encephalomyelitis with a fatality rate of approximately 70%. This infection remains an uncommon result of macaque-related injuries, although the increase in the use of macaques for research on simian retrovirus infection and hepatitis has expanded the number of opportunities for human exposure. In response to this situation, Emory University and the Centers for Disease Control and Prevention jointly sponsored a B Virus Working Group to formulate a rational approach to the detection and management of human B-virus infection. The resulting guidelines are presented herein and are based upon information from published cases, unpublished cases managed by working-group members, knowledge of the behavior of herpes simplex virus, and--in the absence of hard data--the collective judgment of the group. Although consensus among the co-authors existed on the major points covered by these guidelines, opinions varied widely regarding specific recommendations.

Guidelines for the Prevention and Treatment of B-Virus Infections in Exposed Persons

The present invention provides recombinant replication-defective adenoviral vectors derived from chimpanzee adenoviruses and methods for generating recombinant adenoviruses in human E1-expressing cell lines. The invention also provides compositions and methods suitable for use for the delivery and expression of transgenes encoding immunogens against which a boosted immune response is desired. The invention further provides methods of generating clinical grade vector stocks suitable for use in humans. In a particular embodiment the invention contemplates the use of vectors comprising transgenes which encode tumor associated antigens in vaccines and pharmaceutical compositions for the prevention and treatment of cancer.

Chimpanzee adenovirus vaccine carriers

Although there are several reports on rotavirus inoculation of nonhuman primates, no reliable model exists. Therefore, this study was designed to develop a rhesus macaque model for rotavirus studies. The goals were to obtain a wild-type macaque rotavirus and evaluate it as a challenge virus for model studies. Once rotavirus was shown to be endemic within the macaque colony at the Tulane National Primate Research Center, stool specimens were collected from juvenile animals (2.6 to 5.9 months of age) without evidence of previous rotavirus infection and examined for rotavirus antigen. Six of 10 animals shed rotavirus during the 10-week collection period, and the electropherotypes of all isolates were identical to each other but distinct from those of prototype simian rotaviruses. These viruses were characterized as serotype G3 and subgroup 1, properties typical of many animal rotaviruses, including simian strains. Nucleotide sequence analysis of the VP4 gene was performed with a culture-grown isolate from the stool of one animal, designated the TUCH strain. Based on both genotypic and phylogenetic comparisons between TUCH VP4 and cognate proteins of representatives of the reported 22 P genotypes, the TUCH virus belongs to a new genotype, P[23]. A pool of wild-type TUCH was prepared and intragastrically administered to eight cesarean section-derived, specific-pathogen-free macaques 14 to 42 days of age. All animals were kept in a biocontainment level 2 facility. Although no diarrhea was observed and the animals remained clinically normal, all animals shed large quantities of rotavirus antigen in their feces after inoculation, which resolved by the end of the 14-day observation period. Therefore, TUCH infection of macaques provides a useful nonhuman primate model for studies on rotavirus protection.

Development of a Rotavirus-Shedding Model in Rhesus Macaques, Using a Homologous Wild-Type Rotavirus of a New P Genotype

98 antisera prepared against 25 simian adenoviruses and 31 adenovirus types from various nonprimate mammals and birds were tested for their ability to neutralize 35 human adenovirus prototypes. Antise

Immunological Relationship among Adenoviruses of Humans, Simians, and Nonprimates as Determined by the Neutralization Test

Sera from nonhuman primates, predominantly Macaca species, were assayed by a serum neutralization test for antibodies to antigenically related Herpesvirus simiae (B virus) and Herpesvirus hominis type 1 The data indicate that there would have been approximately 50% error in the diagnosis of Herpesvirus simiae infection if these sera had been tested only against Herpesvirus hominis antigen The role of active guinea pig complement in the serum neutralization test was also evaluated and found to be required by many of the sera for reproducible and enhanced virus neutralization, particularly for B virus antibody determination A plaque reduction assay was found to be highly sensitive, especially when complement (25-50 hemolytic units) was added, but impractical for large-scale serum surveys

Detection of antibodies to Herpesvirus simiae and Herpesvirus hominis in nonhuman primates.

A recent survey of nonhuman primate sera indicated that antibody to a rotavirus (SA11) was prevalent among a wide spectrum of animals. Both New and Old World species were found with antibody, many with surprisingly high titers (1:320). Whether or not infection per se was due to SA11 or an antigenically closely related agent could not be determined by that study; however, it is apparent from this study as well as from a survey of the literature that natural as well as experimental infection of nonhuman primates occurs. Recognizing that there is a need for an animal model for the study of viruses associated with human diarrhea, a preliminary investigation attempting to ascertain the susceptibility of the baboon (Papio cynocephalus) to a rotavirus was undertaken. Inoculation of four newborn baboons with SA11 resulted in diarrhea within 24 to 48 hours in all animals. One animal died 10 days postinoculation following severe diarrhea and dehydration. Virus was isolated as well as seen by electron microscopy in the stools of all four animals.

Infection of baboons ("Papio cynocephalus") with rotavirus (SA11).

The presence of herpesviruses in various animal tissues used for vaccine production is of importance, inasmuch as these viruses may go unrecognized, residing in latent form. Of greatest concern is Herpesvirus simiae (B virus) present in the majority of macaca species, one of the more extensively used laboratory nonhuman primates. The close antigenic relationship of B virus to human herpes strains (H. hominis) and SA8 (a baboon herpesvirus) makes serologic differentiation extremely difficult, but necessary. Complicating the differential diagnosis is the frequent infection of simian species with human strains. The present study clearly shows that many animal sera negative to herpes simplex will be negative to B virus in the neutralization test. However, a sufficient number of sera will be negative to simplex, but positive to B virus, indicating that the assumed one-way cross is invalid. Also, if antibody to simplex is present, and this antibody is present in most adult macaques, then differentiation requires testing with B virus. At least 50% of these positive sera may appear to be negative for B virus if only tested with H. hominis. Approximately 25% of the remaining positive sera will have higher titers to B virus than to herpes simplex and 25% will have the same titers to both viruses. Further, complement is required by many of the test sera to detect the presence of antibodies to B virus.

Serodiagnosis of herpesvirus infection in primates.

An enzyme immunoassay (EIA) was used for the detection of antibodies to Herpesvirus hominis type 1 and 2 (HVH-1 and HVH-2), SA8 and Herpesvirus simiae (HVB) in human and nonhuman primate sera. Optimal assay conditions were approximately the same for HVH-1, HVH-2, and SA8 but different for HVB. The recognized lethality of HVB required studies to determine whether or not inactivated HVB could be used in the EIA outside a biohazard safety cabinet. Ten percent buffered formalin destroyed infectivity of antigen coated discs after 5 minutes while retaining activity in the EIA. Antibody titers to HVB determined by serum neutralization were up to eightfold higher in the EIA. Using EIA to survey sera for antibodies to herpesviruses, it was determined that most humans reacted to HVH-1 (88%), HVH-2 (81%) and SA8 (94%), and 38% to HVB. Whereas baboons reacted almost exclusively to their indigenous herpesvirus SA8 (44%), rhesus monkeys demonstrated a high positive rate to HVH-1 (63%), SA8 (94%), and HVB (50%). These data indicate that EIA is rapid, sensitive, reproducible, and useful in the detection of antibodies to human and nonhuman primate herpesviruses but does not, at this point, resolve problems related to cross-reactivity among these viruses.

Detection of primate herpesvirus antibodies including Herpesvirus simiae by enzyme immunoassay.

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