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Experimental infections of humans with wild-type adenoviruses and with replication-competent adenovirus vectors: replication, safety, and transmission

Abstract

Replication-competent (RC) adenoviruses (Ads) are increasingly being developed as oncolytic vectors and as vehicles for delivering vaccine antigens. Although the safety of such vectors in humans is of paramount importance, these vectors pose additional special concerns. Specifically, the prospect of causing Ad-mediated disease in the patient, the amount and sites of Ad replication, the possibility of virus shedding leading to unintended transmission to patient contacts, and the potential for persistence in the inoculated individual must be evaluated. Previous experience with administration of wild-type and RC recombinant Ads to humans may shed light on some of these issues. Experimental infections of humans with natural Ad isolates and RC recombinant vectors show that in adults Ads cause mild or no disease, particularly with Ad serotypes 2 and 5, the serotypes most often used to make recombinant constructs. Other studies show that Ad can replicate in experimentally infected persons, that in some situations Ads can be shed and transmitted to close contacts, and that there is evidence for persistent/latent Ad infection in naturally infected individuals. Overall, these studies indicate that Ads can be safely administered to humans for the treatment of cancer and as antigen delivery vehicles suggesting that the continued development of RC oncolytic and vaccine vectors should be pursued.

Experimental infections of humans with Ad, although limited in scope and number, have provided the scientific community with valuable information regarding Ad natural history of infection and the safety and efficacy of treatments that utilize Ad as a vehicle. Shortly after the initial isolation of Ads in 1953–19541, 2, 3 experimental human infections were aimed at understanding the natural history of infection, determining Ad infectivity, developing anti-Ad vaccines to prevent Ad-mediated disease, and using Ad to treat cancer. With the advent of recombinant DNA techniques capable of altering the Ad genome, the use of RC recombinant Ads for experimental infections of humans and chimpanzees was initiated. These studies have primarily focused on generating vaccines against various infectious diseases by making recombinant Ads that express foreign antigens and on developing anticancer treatments by creating Ad vectors that selectively kill cancer cells. This report summarizes what is known about the experimental infection of humans (and in some cases chimpanzees and mice) with non-attenuated natural isolates of Ad and with RC recombinant Ad vectors. Experimental infections with Ad have shown that Ad causes mild disease symptoms in adults, if any at all, that Ad can be safely administered to humans, and that intimate physical contact is required for horizontal transmission of Ad administered by enteric-coated tablets. Studies in mice show that Ad is not vertically transmitted. Evidence suggests that Ad can persist in some human tissues.

Ad nomenclature

Ads are organized according to the subgroup to which they belong. There are six subgroups, A through F, that are defined by a number of properties including DNA sequence. The members of each subgroup can be distinguished based on serological differences and are thus referred to as serotypes. There can be significant differences in the pathogenicity and course of disease among different serotypes.4 In this article only certain serotypes are discussed. The subgroup assignment of these serotypes is as follows: Ad3, Ad7, Ad16, and Ad21 are in subgroup B; Ad1, Ad2, Ad5, and Ad6 are in subgroup C; Ad8, Ad 9, Ad10, Ad26, and Ad27 are in subgroup D; and Ad4 is in subgroup E.

Natural history of Ad infection

In one of the earliest accounts of an experimental infection of humans with Ad, adult volunteers infected with filtered nasopharyngeal excretions from patients with Acute Respiratory Disease (ARD) or nasopharyngeal catarrh exhibited only mild nasal inflammation and congestion.5 In the early to mid-1950s, a series of studies was conducted aimed at determining what type of illness(es) Ads could induce in humans (Bell et al6 and references therein). These studies showed that experimentally infected volunteers infrequently exhibited minor respiratory illness following intranasal administration of Ad types 1, 2, 3, 5, and 6. The illness could not be definitively ascribed to Ad infection despite serological evidence of infection.6 Importantly, one of these studies, conducted at the Federal Industrial Reformatory at Chillicothe, Ohio, found that no respiratory disease outbreaks occurred among the reformatory population either immediately before, during, or after the experimental infections, suggesting that virus was not transmitted to noninoculated persons by casual contact with experimentally infected individuals.6 Another study with Ad1 confirmed that intranasal inoculation of this serotype in humans lacking pre-existing neutralizing antibodies caused acute pharyngitis characterized by nasal exudates, sore throat, headache, and cervical adenitis.7 Further experimental infections in which the eye was infected by conjunctival swabbing resulted in an illness similar to pharyngoconjunctival fever that was attributable to the inoculated Ad types 1, 3, 4, and 5.6, 8 Pharyngoconjunctival fever is characterized by any combination of fever, pharyngitis, and conjunctivitis.

Studies by Couch et al9, 10 demonstrated that inhalation of Ad4 formulated as either a small or large particle aerosol can induce illness in human volunteers. The small particle aerosol was more efficient at inducing illness than the large particle aerosol10 and could occur by inhalation of just a few virus particles.9 The induced illness was similar to that seen in military recruits suffering from ARD and suggested that ARD is contracted by inhalation into the lower respiratory tract of Ad that has been aerosolized by coughs and sneezes of infected persons.9

Experimental infections of human volunteers with other less-common Ad serotypes have been reported. Inoculation with Ad type 8 (Ad8) of the conjunctiva of adult human volunteers showed that this serotype caused mild to severe illness in individuals that did not have naturally acquired pre-existing neutralizing antibodies to Ad8; the illness consisted of acute follicular conjunctivitis, preauricular adenopathy, and punctate keratitis.11, 12 The clinical symptoms were self-limiting and were consistent with those of naturally acquired epidemic keratoconjunctivitis, strongly suggesting that Ad8 is the etiological agent of this disease. The course and severity of disease in a laboratory worker accidentally infected with Ad8 was consistent with the clinical observations described above.13 Experimental inoculation of Ad type 16 into the conjunctiva of several volunteers resulted in self-limiting, afebrile, nonpurulent conjunctivitis that was similar to natural Ad16 infections with respect to symptoms and severity.14 Intranasal inoculation of Ad26 and Ad27 resulted in only very mild rhinitis but conjunctival swabbing of these serotypes caused conjunctivitis.15 Neither route of administration caused systemic disease despite evidence of a prolonged period of virus recovery from rectal specimens.15 The conjunctivitis caused by Ad26 and Ad27 was self-limiting, mild to moderate in severity, limited to the eye, and characterized by palpebral and bulbar erythema and in more severe cases severe eye pain, edema, and preauricular adenopathy, with symptoms generally being slightly more severe for Ad27 than Ad26.15 Unlike ocular infection with Ad4, Ads 16, 26, and 27 did not cause keratitis.15

Overall, these early clinical studies using healthy human volunteers show that infection with natural, nonattenuated isolates of Ad did not cause severe disease. Ad infection induced mild respiratory illness when inoculated intranasally (Ad types 1, 2, 3, 5, and 6), caused ARD when inhaled (Ad4), and produced conjunctivitis when inoculated into the eye (Ad types 1, 3, 4, 5, 8, 16, 26, and 27). Importantly, Ad-induced disease was self-limiting and rarely required medical intervention.

Replication-competent adenovirus vaccines

Following the identification of Ad as the agent of ARD, vaccines against Ad types 4, 7, and 21 (the three most common causative agents of Ad-induced ARD) were developed that consisted of live, nonattenuated isolates of Ad4, Ad7, and Ad21.16, 17, 18, 19, 20, 21, 22 The live virus contained in these vaccines is formulated as an enteric-coated capsule or tablet and upon oral administration causes an asymptomatic infection in the gut16, 17 that results in repeated virus shedding in the stool of vaccinees for 2–3 weeks following vaccination.23 These enterically administered vaccines do not result in replication of the vaccine virus in the upper respiratory tract.17, 24, 25 With hundreds of thousands of vaccinated US military recruits these vaccines have proven to be highly efficacious and have an excellent safety record.26

Owing to replication of the live Ad4 vaccine virus in immunized individuals, several studies were conducted to examine the possibility that vaccine virus could be transmitted to nonimmunized people. Initially, studies with nonvaccinated military personnel who shared the same barracks as vaccinees (including eating and toilet facilities) showed that the Ad4 vaccine virus did not spread to nonimmunized individuals.17, 23, 25 Another study showed that oral or nasal administration of the Ad4 vaccine did not result in transmission to naïve subjects housed in the same quarters.27 However, subsequent reports in different settings indicated that Ad4 vaccine virus could be transmitted to nonimmunized contacts of vaccinees.28, 29 A study of childless married couples where only one partner received the Ad4 vaccine showed clear evidence of virus spread to the nonimmunized partner.28 In a family setting, virus was not transmitted from immunized mothers to their partner (most of whom already had serum neutralizing antibodies against the immunizing virus serotype) or to their children, but virus was spread from vaccinated children to his/her mother and to other child contacts.29 Infections of contacts were asymptomatic and it was presumed that the route of infection was oral–fecal. It was hypothesized that due to the enteric nature of the infection with the vaccine virus (versus infection of the oropharynx with natural infection) that intimate physical contact was required for transmission of the vaccine virus to susceptible contacts.29

Because Ad types 1, 2, and 5 are etiologically important in pediatric respiratory disease and because vaccination against Ad types 4 and 7 successfully controls ARD in military recruits, vaccines against Ad types 1, 2 and 5 were also evaluated in humans.30 This small vaccination study showed that live Ad1, Ad2 or Ad5 vaccine administered to adults by enteric coated tablets produced active infection, as demonstrated by virus shedding in the stool, was safe since no clinical illness or adverse affects were noted, and generated serum neutralizing antibody in the majority (77–88%) of subjects.30 In contrast to results with the Ad4 and Ad7 vaccines, some replication in the pharynx was observed upon enteric administration of the Ad2 and Ad5 vaccines.30

An experimental live nonattenuated vaccine against Ad type 8 was also tested in a small number of human volunteers. Intradermal inoculation of the vaccine virus did not cause any signs of disease. When inoculated with a sufficient quantity of vaccine virus, people were protected from homologous, but not heterologous (Ad3) ocular challenge.12

Because of the success and safety of the Ad4 and Ad7 vaccines, the possibility of generating live recombinant Ad vaccines to combat other infectious diseases has been explored. In particular, research has focused on developing vaccines against hepatitis B virus and human immunodeficiency virus type 1 (HIV-1). In addition to studies in small animals, enteric-coated vaccines were tested in humans and chimpanzees, which were shown to be susceptible to Ad infection in the gut after oral administration of the vaccine.31

Recombinants of Ad4, Ad5, and Ad7 that express the hepatitis B surface antigen were generated and tested in chimpanzees.31, 32, 33 During these trials, no signs of illness that were attributable to the vaccine were noted. Of particular interest are two reports presenting evidence that an intact E3 region resulted in increased replication of the vaccine virus;32, 33 the E3 region encodes proteins whose function is to protect infected cells from the immune system.34 In addition, an Ad7-based vector expressing hepatitis B surface antigen was tested for safety in humans.35 The authors reported no illness or adverse clinical reactions that were attributable to the vaccine. The human trial was conducted in an isolation ward in which placebo and vaccinee recipients shared eating and recreation facilities. Importantly, there was no evidence for transmission of vaccine virus from vaccinees to placebo recipients.35

Live recombinant Ads expressing HIV-1 envelope (gp160) or gag proteins have been constructed and tested for safety and efficacy in chimpanzees. Intranasal administration of recombinant Ad4, Ad5, and Ad7 vaccines to chimpanzees resulted in no signs of respiratory or enteric illness despite evidence for Ad replication (virus recovered in stool and development of anti-Ad neutralizing antibodies).36 Another investigation found similar results37 suggesting that these vaccine viruses are safe and do not cause overt illness in chimpanzees even though active replication in the gut occurs.

Adenovirus persistence and latency

It has long been speculated that Ads are able to establish persistent and/or latent infections in humans. The fact that in 25–90% of cases Ad can be grown from excised adenoids and/or tonsils after an extended culture period first suggested that these organs are persistently/latently infected.1, 2, 38, 39, 40, 41, 42, 43, 44 Ads isolated from adenoids and tonsils were almost exclusively types 1, 2, 5, and 6, although types 3, 4, and 7 have also been isolated. A report that infectious Ad could not be demonstrated in tonsils that were positive for Ad DNA by in situ hybridization (ISH) further supports the idea of Ad latency.45 Epidemiological studies showing that Ad can be detected in fecal specimens for months to years after initial infection also suggest that Ads establish persistent/latent infections.46, 47 Furthermore, using various hybridization techniques, Ad sequences have been detected in DNA isolated from human tonsils48 and peripheral blood lymphocytes49 and in RNA isolated from placenta.50

Evidence that Ads are capable of setting up persistent and/or latent infection of the lung comes from studies of lung tissue. The lungs of patients with chronic obstructive pulmonary disease (COPD) showed a greater level of Ad DNA (by PCR) than those of age, sex, and smoking history matched controls.51 Immunohistochemistry52 and ISH (in situ hybridization)51 were used to demonstrate that E1A protein expression and Ad DNA, respectively, was localized to lung epithelial cells of smokers with COPD. Another study showed that E1A protein expression was increased in the alveolar epithelial cells of patients with emphysema in proportion to disease severity (more severe disease showed greater E1A expression).53 Further, PCR and ISH were used to demonstrate latent/persistent Ad infection in patients with bronchiectasis.54 Immunofluorescence and virus isolation assays were used to show that the majority of bronchoalveolar lavage specimens from children with chronic airway obstruction were infected with Ad, whereas control patients did not show signs of Ad infection.55 One study showed that an equal proportion of patients who died of fatal asthma, asthmatic patients who died of other causes, and nonasthmatic patients who did not die of lung disease were positive for Ad DNA (by PCR) in lower airway secretions obtained at autopsy.56 In a study of specimens obtained by nasopharyngeal swabs of normal and asthmatic children at least 3 weeks from their last respiratory infection, Marin et al57 found that 5% (one out of 20) of normal but 78% (69 out of 88) of asthmatic samples were positive for Ad by PCR.

Several studies used PCR to detect Ad DNA in various lung tissue specimens. Ad DNA was detected in nasal epithelial, bronchial epithelial, and bronchoalveolar lavage cells isolated from normal volunteers (21%) or cystic fibrosis patients (13%).58 Ad DNA was present in tumor tissue from patients with small-cell lung carcinoma (31%; 11 out of 35 cases) but not nonsmall-cell lung carcinoma (0%; out of 0 of 40).59 A variable proportion of lung tissue specimens from patients with idiopathic pulmonary fibrosis, interstitial pneumonia associated with collagen vascular disease, and sarcoidosis were positive for Ad DNA, although there appeared to be no causal relationship.60 Overall, the studies cited above suggest that Ad may persist and/or become latent in the tonsils, adenoids, or lungs of infected individuals.

The sites of latent/persistent infection have not been investigated thoroughly, but evidence suggests that lymphocytes are a possibility.43 Tonsils and adenoids, from which Ad can be cultured (see above), are comprised predominantly of lymphoid cells. Although lymphocytes are difficult to infect with Ad in vitro, evidence that these cells are latently/persistently infected has been reported. Ad DNA was detected peripheral blood lymphocyte samples by Southern blot analysis and ISH.49 Supporting evidence was provided by Flomenberg et al,61 who isolated a B-cell lymphoma from a patient that was persistently infected with Ad. In contrast, only one out of 73 PBMC samples were positive for Ad DNA using a PCR assay.62 In a recent study, Ad DNA was frequently detected (by real-time PCR) in lymphocytes purified from tonsils and adenoids (79%) despite the fact that infectious virus was rarely observed in these same samples.63 Using antibody depletion methods, these authors demonstrated that Ad DNA was enriched in CD8/CD4-expressing and/or CD3-expressing T cells, while B cells expressing CD19 were devoid or depleted of Ad DNA.63 However, as described above, lung epithelial cells may also be a site of latent/persistent Ad infection.

Replicating adenoviruses as anticancer agents

Three publications report the use of nonattenuated strains of Ad for the treatment of human cancer. The first reported use of Ad for treatment of cancer occurred in 1956,64 shortly after the initial discovery of the virus. In all, 30 patients with carcinoma of the cervix were inoculated by four different routes with undetermined amounts various Ad serotypes (1–7, and 10). In addition, some patients were treated with cortisone. Although none of the treatments altered the ultimate disease outcome, only administration of live Ad (not heat-killed Ad or tissue culture medium) resulted in frequent (65% of inoculations) tumor necrosis and cavity formation within the tumor. Treatment with Ad was tolerated well in these patients, with only three patients showing marked Ad-induced symptoms that included fever, malaise, and photophobia. While nearly all patients showed elevated levels of neutralizing antibodies suggesting that the inoculated virus replicated in the patient, virus was recovered from only two thirds of the patients.64

In the second report, 14 patients with various types of cancer were infected with Ad4 through various routes (intranasal, intramuscular, intradermal, intratracheal, or by inhalation).65 Virus administration caused only minor clinical symptoms. Only one patient, who was inoculated intratracheally, showed signs of respiratory tract infection; he developed tracheitis with a mild fever that persisted for 3 days starting 7 days after virus treatment. One patient showed the following symptoms for 1 week starting on the day of injection: low-grade fever, malaise, anorexia, nausea, and vomiting. Two patients that received intramuscular injection developed low-grade fever. Despite the fact that virus was recovered only once out of 44 attempts, (the virus was recovered from the tumor tissue of a patient 5 days after intratumoral inoculation) all patients who survived beyond 8 days postinoculation developed or showed an increase in anti-Ad4 antibodies suggesting active infection in all patients. Two patients who received intramuscular injection (the same two who experienced fever) exhibited signs of transient tumor regression; otherwise, no beneficial effect of virus treatment was noted.

The third study involved intratumoral and/or intravenous inoculation of different Ad serotypes (types 1–7 and 9) into 10 patients terminally ill with cervical cancer.66 As in the two previous studies, clinical signs of infection, which included fever, chills, joint and abdominal pain, and fatigue, were evident in only some patients and were minor and transient. Signs of respiratory or eye infection were absent. In four patients who received adrenocorticotropic hormone, the symptoms were more pronounced. Virus isolation from inoculated patients was not reported. Of the three patients who received only virus therapy, one showed clear but transient evidence of tumor cell necrosis (this patient died 6 months after virus treatment), one had no immediate clinical change but later progressed, and one showed progressive disease. Considerable tumor cell destruction was observed in six of seven patients who underwent radiation treatment following virus therapy suggesting that virus treatment sensitized tumor cells to subsequent radiotherapy. Of these seven patients, two showed progressive disease, while five showed stable disease or regression for 16–24 months. A 10-year follow-up indicated that four out of the 10 patients were still alive and appeared disease free.67

The use of replicating Ads has gained momentum recently because of an increased understanding of the role of Ad-encoded and cellular proteins in the viral replication cycle,68 and a better grasp of the genetic and biochemical changes that occur in malignant cells.69, 70, 71, 72 Promising results in preclinical testing of several conditionally replicating adenovirus vectors warranted phase I and phase II clinical trials. ONYX-015 (dl1520 or CI-1042), which preferentially replicates in cells with a deregulated cell cycle due to a deletion of the E1B-55 K gene,73 has been evaluated for several indications including recurrent head and neck squamous cell carcinoma, pancreatic carcinoma, solid tumors of various origins metastatic to the lung, metastatic colorectal carcinoma, and ovarian cancer. The results of 17 phase I and phase II clinical trials using ONYX-015 or dl1520 have been published.74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 The vector CG7060 (CV706) is a prostate-specific antigen (PSA)-selective replication-competent virus that is indicated for use in prostate cancer.91 A single Phase I clinical trial with CG7060 has been reported.92 CG7870 (CV787) is another vector that is intended for use in prostate cancer.93 The results of one Phase I trial has been reported at a meeting, but not yet published in a peer-reviewed journal.94 A fourth vector, named Ad5-CD/Tkrep, is the first replication-competent adenovirus vector that expresses a therapeutic gene to be tested in humans.95, 96 Ad5-CD/Tkrep is replication selective because it contains the same E1B-55K gene deletion as dl1520, and the vector expresses a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (TK) fusion gene to allow for therapeutic treatment with both 5-FC and ganciclovir.97 A clinical trial for yet another replication-competent Ad vector, Ad-OC-E1a (also called OCaP1), has been proposed for the treatment of refractory osteosarcoma metastatic to the lung.98 This Ad vector replicates conditionally because the mouse osteocalcin promoter controls expression of the E1A gene.99

Of paramount importance in the development of virus vectors for the treatment of cancer is careful assessment of the safety and toxicity of these agents in humans. This issue was underscored recently because of the death of a patient with ornithine transcarbamylase deficiency who was enrolled in a Phase I clinical trial using a replication-defective Ad vector that expresses ornithine transcarbamylase.100 This patient was injected with a large amount (3.8 × 1013 particles) of vector that apparently led to a cytokine cascade, which resulted in death due to a vector-induced shock syndrome consisting of disseminated intravascular coagulation, acute respiratory distress, and multiorgan failure.100 The use of replication-competent Ad vectors poses a special concern since replication of the virus in the patient should lead to an enhanced level of and prolonged exposure to virus and thus, might increase the chances of virus-induced toxicity. Related to this concern are several reports indicating liver toxicity following Ad vector administration in preclinical models, including with ONYX-015.101, 102, 103

To address this matter, special attention has been paid to the assessment and reporting of virus-induced toxicity in the clinical trials that have been conducted with replication-competent Ad vectors. In clinical trials of ONYX-015, the virus was well tolerated with only minimal grade 3 and grade 4 toxicities reported (Table 1) and no study-related deaths have been reported. Thus, ONYX-015 appears to be safe in humans at up to 1 × 1013 virus particles per injection. When CG7060 was injected intraprostatically at doses from 1 × 1011 to 1 × 1013 virus particles per injection, there were no grade 3 or grade 4 toxicities associated with treatment, no DLT was reported, and the MTD was not reached (Table 2).92 Thus, CG7060 appears to be well tolerated at the doses tested. The results of two clinical trials with Ad5-CD/tkrep show that at doses of up to 1 × 1012 particles this vector is tolerated well and resulted in only a minimal number of grade 3 toxicities and no grade 4 toxicities (Table 2). It is encouraging that no significant respiratory, liver toxicities, or clotting abnormalities attributable to a replication-competent Ad vector have been reported in the clinical trials published to date.

Table 1 Clinical trials with ONYX-015
Table 2 Clinical trials with CG7060 or Ad5-CD/Tkrep

Of particular concern with respect to replication-competent Ad vectors is the potential for unintended spread of the vector from the inoculated patient to his/her contacts. Any factors that enhance the likelihood of virus shedding (i.e. release of virus into the environment) could increase the chance for spread of the vector to close or even casual contacts of the inoculated patient. Two factors that might have a bearing on this matter are the level of vector replication in the host and the route of virus administration. Replication of the vector within the patient would create a larger pool of virus that could possibly be shed. The route of virus administration could affect the likelihood of shedding by perhaps restricting virus replication to body compartments that do not have ready access to the environment. Published clinical trials have shed some light on these issues.

To investigate whether virus has actually replicated in inoculated individuals, researchers have used sensitive PCR techniques to detect viral DNA and in situ hybridization and electron microscopy of biopsy specimens to detect viral DNA or proteins. It has been argued that detection of virus by PCR of blood samples may have simply detected virus that is part of the inoculum.104 To counter this point, it was shown that intra-arterially injected ONYX-015 was cleared from the blood stream by 6 hours postinjection and that in one clinical trial, the level of ONYX-015 in three patients was higher at 48 hours than at 6 hours postinjection.76, 105 Viral DNA detected by PCR analysis of blood samples from patients injected intra-arterially, intravenously, intratumorally, or intraprostatically has provided some support for virus replication.75, 76, 78, 81, 83, 86, 90, 92, 95, 96 In addition, one study showed that virus was detected by PCR of peritoneal washes in patients injected intraperitoneally.85 However, the inability to detect viral DNA in the blood following intratumoral or intraperitoneal administration of virus has also been reported.80, 85, 87, 88 Detection of viral DNA in some tumor biopsy specimens by in situ hybridization or PCR has also suggested viral replication in tumor tissue but not in surrounding normal tissue.74, 75, 77, 87, 89, 90, 92, 95, 96 However, in situ hybridization has given negative results in some cases.76, 80, 88, 95, 96 Electron microscopy analysis of biopsy specimens has also provided evidence for ONYX-015 and CG7060 replication.89, 90, 92 In one study, viral DNA (by PCR) and protein (by immunohistochemistry) were detected in postmortem tissue samples of a single patient whose death, which occurred 56 hours after her third intravenous ONYX-015 treatment, was attributed to progression of her pancreatic cancer.81 Interestingly, the highest levels of virus were detected in the spleen and in nonmalignant liver cells, with only low levels of viral DNA and antigen detected in tumor tissue.81

Only a few clinical trial reports have directly addressed the question of virus shedding from inoculated patients. ONYX-015 was not detected from swabs taken from the oropharynx or injection site on days 0, 8, 15, 22, and 29 following virus injection.87 In another study, following intratumoral ONYX-015 injection of hepatobiliary tumors, the vector was never detected in the urine of patients, but was present in two out of two bile samples, suggesting that examination of stool samples for the presence of vector may be warranted.82 The amount of infectious CG7060 excretion into the urine was measured by plaque assay following intraprostatic injection of the vector. CG7060 was detected in the urine of patients on days 2 (11 out of 19 patients) and 8 (two out of 19 patients) but was not detected on days 19 and 29 postinjection.92 In addition, viral DNA but not infectious vector was detected in the urine of patients who were intraprostatically injected with Ad5-CD/Tkrep.95 These data indicate that under some conditions vector can be shed from inoculated patients.

Vertical transmission

The use of a live DNA virus as a vaccine or cancer therapeutic agent presents the possibility of infection of germline cells and, if integrated into the host cell chromosome, vertical transmission. Several studies have addressed the question of Ad replication in cells of the reproductive system and the potential for germline transmission. One study found that despite the presence of the Ad receptor CAR (Coxsackie Adenovirus Receptor) on mouse germ cells, these cells were not highly infectable with a replication-defective Ad vector either in vivo or in vitro.106 These authors also found that after intraventricular injection, Ad was only transiently detected within the testes (between 4 and 14 days). Another group reported that even though a low level of replication-defective Ad vector could be detected in the gonads of mice injected via the tail vein, the gonad-associated virus was not vertically transmitted.107 A third study showed that a replication-competent Ad vector injected intraprostatically into mice was able to persist in the testes for up to 28 days postinjection but that mice mated during this time frame did not transmit the virus to their progeny.108 Together these findings suggest that although systemically administered Ad can disseminate to reproductive organs, the virus is not vertically transmitted in mice. No evidence for vertical transmission of Ad in naturally or experimentally infected humans was uncovered in the literature.

Summary

During the last 50 years live nonattenuated natural Ad isolates and recombinant Ad vectors have been experimentally administered to human volunteers. These experimental infections have shown that Ad causes upper respiratory tract infections that are characterized by mild cold-like symptoms when inoculated intranasally (primarily subgroup C Ads), ARD when small particle aerosol of Ad4 is inhaled, and conjunctivitis when administered by conjunctival swabbing (various Ad serotypes). When enteric-coated tablets or capsules are given orally, Ads generally produce asymptomatic infections of the gut (and sometimes the pharynx). Injection of people with natural Ad isolates or replication-competent recombinant Ad vectors for the treatment of cancer has also been reported. These cancer treatment studies indicate that Ad can be safely administered to human subjects even when there is evidence for virus replication. Overall, Ads have proven to be safe when experimentally inoculated into humans or chimpanzees.

The horizontal and vertical spread of experimentally inoculated Ad has not been extensively studied, but several investigations have been conducted. Studies in human volunteers suggest that transmission of orally inoculated vaccine virus from vaccinees to close contacts requires intimate physical contact probably due to the enteric nature of the infection. In addition, there have been two reports of Ad being excreted in the urine of patients that had been intraprostatically injected with a replication-competent Ad vector. Studies in mice show that systemically or intraprostatically administered Ad can be found in the reproductive organs of mice. However, vertical transmission in mice has not been demonstrated despite the fact that mouse germ cells express CAR and some germ cell types can be infected.

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Acknowledgements

We thank Dr Dorota Skowyra for the Polish to English translation of reference number 67. This work was supported by Grants CA081829, CA108335, CA108046, and CA108046 from the National Institutes of Health.

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Correspondence to William S M Wold.

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Lichtenstein, D., Wold, W. Experimental infections of humans with wild-type adenoviruses and with replication-competent adenovirus vectors: replication, safety, and transmission. Cancer Gene Ther 11, 819–829 (2004). https://doi.org/10.1038/sj.cgt.7700765

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Keywords

  • adenovirus
  • replication-competent vectors
  • human
  • clinical trials
  • review

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