Chimpanzee adenovirus antibodies in humans, sub-Saharan Africa.Human sera from the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. , Thailand, and sub-Saharan Africa and chimpanzee chimpanzee, an ape, genus Pan, of the equatorial forests of central and W Africa. The common chimpanzee, Pan troglodytes, lives N of the Congo River. Full-grown animals of this species are up to 5 ft (1. sera were tested for neutralizing antibodies to 3 chimpanzee adenoviruses. Antibodies were more common in humans residing in sub-Saharan Africa than in humans living in the United States or Thailand. This finding suggests cross-species transmission of chimpanzee adenoviruses. ********** Vaccines to HIV-1 are needed to stem further spread of the HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. pandemic pandemic /pan·dem·ic/ (pan-dem´ik) 1. a widespread epidemic of a disease. 2. widely epidemic. pan·dem·ic adj. Epidemic over a wide geographic area. n. . One vaccine modality modality /mo·dal·i·ty/ (mo-dal´i-te) 1. a method of application of, or the employment of, any therapeutic agent, especially a physical agent. 2. that has shown promise is based on adenovirus adenovirus Any of a group of spheroidal viruses, made up of DNA wrapped in a protein coat, that cause sore throat and fever in humans, hepatitis in dogs, and several diseases in fowl, mice, cattle, pigs, and monkeys. vectors of human serotype serotype /se·ro·type/ (ser´o-tip) the type of a microorganism determined by its constituent antigens; a taxonomic subdivision based thereon. se·ro·type n. See serovar. v. 5 (AdHu5) (1-3). However, immune responses induced by AdHu5 vectors are reduced by preexisting pre·ex·ist or pre-ex·ist v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists v.tr. To exist before (something); precede: Dinosaurs preexisted humans. v.intr. AdHu5-neutralizing antibodies found in humans in the United States (4-7). The Study To circumvent the negative effect of preexisting immunity to common human serotypes of adenoviruses on the efficacy of adenovirus vaccine carders, we developed vectors based on chimpanzee-derived adenoviruses C68, C6, and C1 (8). We previously showed that neutralizing antibodies to chimpanzee adenoviruses are rarely found in US residents (6). Because vaccines to HIV-1 are most urgently needed in sub-Saharan Africa, we evaluated the prevalence of neutralizing antibodies to chimpanzee adenoviruses in sera from humans residing in 3 sub-Saharan countries with natural habitats for chimpanzees: Nigeria, Cameroon, and Cote d'Ivoire. Sera from captive chimpanzees in the United States and human sera from Thailand and the United States, including samples from persons with known exposures to chimpanzees, were tested for comparison. Neutralizing antibodies to AdHu5 were found in most serum samples from Africa and Thailand. Percentages of antibodies to AdHu5 were higher in serum samples from Africa and Thailand than in serum samples from the United States (Table 1). Titers to AdHu5 were comparable in serum samples from the United States and sub-Saharan Africa but were higher in the control group from Thailand (Table 2). Neutralizing antibodies to AdC68, AdC6, and AdC1 were rare in sera from the United States and Thailand, with prevalence rates from 1.5% to 4% (Figure). Most positive samples had titers <80. Of 200 samples from Thailand, only 6 had high titers: 4 to AdC6 and 2 to AdC1. None of the samples from 50 US zoo workers, including those who reported regular contact with primates, had detectable antibodies to chimpanzee adenoviruses. In contrast, serum samples from sub-Saharan African cohorts had higher prevalences of neutralizing antibodies to chimpanzee adenoviruses (Figure, Table 1). Samples from persons living in Cameroon and Nigeria showed a higher prevalence of neutralizing antibodies to AdC6 and AdC1. Titers of neutralizing antibodies to AdC6 and AdC1 were high, and samples were positive at dilutions [greater than or equal to] 1:80. When compared with sera from Nigeria and Cameroon, sera from Cote d'Ivoire had a different pattern of antibodies reactive to the chimpanzee adenoviruses; prevalence rates were low to AdC1 but higher to AdC68 and AdC6. Although most samples had low to moderate titers, several samples had titers [greater than or equal to] 80. No association was found between neutralizing antibodies to AdC68, AdC6, and AdC1 in any of the human samples tested, and only a few human serum samples had neutralizing antibodies to [greater than or equal to] 1 chimpanzee adenovirus (data not shown). One serum sample from Cameroon neutralized all 3 chimpanzee adenoviruses and had titers of 20 to AdC68 and 160 to AdC6 and AdC1. [FIGURE OMITTED] Circulating neutralizing antibodies to AdHu5 were found in 44% of captive US chimpanzees; titers in chimpanzee samples were comparable to those in human sera, suggesting that AdHu5 can readily cause an infection in captive chimpanzees. The prevalence of antibodies to AdC6 and AdC68 was high and exceeded that of antibodies to AdC1 (Table 1). Titers to AdC68 and AdC6 were higher in chimpanzees than in humans, but titers to AdC1 in both species were similar (Table 2). Conclusions Our data show that as expected, neutralizing antibodies to chimpanzee adenoviruses are rarely found in humans residing in the United States or Thailand. In contrast, their prevalence is higher in human sera from sub-Saharan Africa, where hunting and butchering of nonhuman primates for food are widespread and eating bush meat is common (11). Different prevalence rates of neutralizing antibodies to the 3 chimpanzee adenoviruses in human samples from the 3 African countries tested may reflect different infection rates in chimpanzees residing in these areas. Cameroon, Gabon, and Republic of Congo are home to most Central African Central African may mean:
see chimpanzee. troglodytes Troglodytes race of uncivilized cave dwellers. [Gk. Hist.: Brewer Dictionary, 1103] See : Coarseness ). Most Western common chimpanzees (P. t. verus) inhabit Cote d'Ivoire and Guinea. The rare Nigeria chimpanzee (P. t. vellerosus) is found only in eastern Nigeria and western Cameroon, and Eastern African common chimpanzees (P. t. schweinfurthii) reside in a range from Central African Republic Central African Republic, republic (2005 est. pop. 3,800,000), 240,534 sq mi (622,983 sq km), central Africa. The landlocked nation is bordered by Chad (N), Sudan (E), Congo (Kinshasa) and Congo (Brazzaville) (S), and Cameroon (W). and the Democratic Republic of the Congo through western Uganda and Tanzania. No clear association was found between chimpanzee subspecies subspecies, also called race, a genetically distinct geographical subunit of a species. See also classification. and neutralizing antibodies to different chimpanzee adenoviruses. Nevertheless, most samples were from P. t. verus, and only a limited number of samples were from P. t. troglodytes (n = 4) and P. t. schweinfurthii (n = 3). No samples from P. t. vellerosus were tested. In addition, the chimpanzee samples evaluated in the study were from animals kept in captivity and thus may not provide information on distribution of these viruses in free-ranging animals. Increased prevalence of neutralizing antibodies to chimpanzee adenoviruses in sub-Saharan Africa may reflect cross-species transmission of these viruses from chimpanzees to humans. If transmission occurs, human-to-human spread of chimpanzee adenoviruses might further contribute to the comparatively high seroprevalence seroprevalence Immunology The proportion of a population that is seropositive–ie, has been exposed to a particular pathogen or immunogen; the seropositivity of a population is calculated as the number of individuals who produce a particular antibody divided seen in equatorial Africa Equatorial Africa is an ambiguous term that is sometimes used to refer to tropical Africa, Sub-Saharan Africa, or the region of Africa traversed by the equator. The term is often used in tropical medicine and climatological discourse, but during colonial times it had a more . Although we have no direct proof for viral cross-species transmission, this process has been previously described for other chimpanzee viruses. For example, the AIDS epidemic is believed to have originated from simian immunodeficiency virus-infected chimpanzees (12). Another chimpanzee retrovirus retrovirus, type of RNA virus that, unlike other RNA viruses, reproduces by transcribing itself into DNA. An enzyme called reverse transcriptase allows a retrovirus's RNA to act as the template for this RNA-to-DNA transcription. , simian foamy virus The simian foamy virus (SFV) is a spumavirus closely related to HIV, the virus that causes AIDS. Its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes and monkeys through hunting , has been reported to infect persons exposed to primates at zoos and research centers (13) and to infect Bantus in Cameroon (14). Chimpanzee adenoviruses do not appear to spread easily to humans through occupational contact with primates because none of the 23 persons who had routine exposure to primates, including chimpanzees, had serologic se·rol·o·gy n. pl. se·rol·o·gies 1. The science that deals with the properties and reactions of serums, especially blood serum. 2. evidence of exposure despite the high prevalence of antibodies to chimpanzee adenoviruses in captive US chimpanzees. Use of chimpanzee adenovirus vectors as vaccines for HIV-1 would require that most persons at high risk for HIV-1 infection lack neutralizing antibodies to these adenoviruses because such antibodies impair induction of transgene transgene a gene that has been incorporated into the genome of another organism. product-specific immune responses (4,5). Even in countries where chimpanzees are endemic, neutralizing antibodies to chimpanzee adenoviruses are less common in humans than those directed to AdHu5, which is currently in clinical trials as a vaccine for HIV-1 antigens in a vectored and replication-defective form. An alternative human serotype is AdHu35, which is being developed as a potential vaccine against HIV-1 (15). Prevalence rates to AdHu35 are low in the United States and Europe (<5%); however, rates are markedly higher (<20%) in equatorial Africa (15). Although neutralizing antibodies to chimpanzee adenoviruses are also relatively more common in human sera from sub-Saharan Africa, they are found less frequently than antibodies to AdHu5 or AdHu35. Nonetheless, increased prevalence of neutralizing antibodies to adenoviruses in countries that are hardest hit by the AIDS pandemic Acquired Immune Deficiency Syndrome (AIDS) has led to the deaths of more than 25 million people since it was first recognized in 1981, making it one of the most destructive epidemics in recorded history. needs to be taken into account in the design of vaccines based on chimpanzee adenovirus vectors. Vectors derived from other species are being developed and may provide additional or alternative vaccine carriers. Acknowledgments We thank H. Wilde, R Marx, and J. Nkengasong for providing human sera; the National Primate Centers for providing chimpanzee sera; and Colin Barth for help in preparation of this article. This study was supported by grant 5P01AI052271-04 from the National Institute of Allergy and Infectious Diseases infectious diseases: see communicable diseases. , National Institutes of Health. Hildegund C.J. Ertl has a patent for the use of adenovirus of the human serotype 5 as a vaccine carrier for HIV-1 infections. She has a similar patent pending for the use of chimpanzee adenovirus vectors (AdC68). References (1.) Xiang ZQ, Yang Y, Wilson JM, Ertl HC. A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology virology, study of viruses and their role in disease. Many viruses, such as animal RNA viruses and viruses that infect bacteria, or bacteriophages, have become useful laboratory tools in genetic studies and in work on the cellular metabolic control of gene expression . 1996;219:220-7. (2.) Shiver JW, Fu TM, Chen L, Casimiro DR, Davies ME, Evans RK, et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature. 2002;415:331-5. (3.) Vinner L, Wee EG, Patel S, Corbet S, Gao GP, Nielsen C, et al. Immunogenicity immunogenicity /im·mu·no·ge·nic·i·ty/ (-je-nis´it-e) the property enabling a substance to provoke an immune response, or the degree to which a substance possesses this property. in Mamu-A*01 rhesus macaques of a CCR 1. CCR - condition code register. 2. CCR - (Database) concurrency control and recovery. 5-tropic human immunodeficiency virus human immunodeficiency virus n. HIV. Human immunodeficiency virus (HIV) A transmissible retrovirus that causes AIDS in humans. type 1 envelope from the primary isolate Primary isolate is a pure microbial or viral sample that has been obtained from an infected individual, rather than grown in a laboratory. In chemistry and bacteriology, the verb isolate means to obtain a pure chemical, bacteriological or viral sample. (Bx08) after synthetic DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. prime and recombinant adenovirus 5 boost. J Gen Virol. 2003;84:203-13. (4.) Fitzgerald JC, Gao GP, Reyes-Sandoval A, Pavlakis GN, Xiang ZQ, Wlazlo AP, et al. A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag. J Immunol. 2003;170:1416-22. (5.) Casimiro DR, Chen L, Fu TM, Evans RK, Caulfield MJ, Davies ME, et al. Comparative immunogenicity in rhesus monkeys of DNA plasmid, recombinant vaccinia virus vaccinia virus n. A virus of the genus Orthopoxvirus used in the immunization against smallpox. , and replication-defective adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene gag gene a gene which encodes precursors of internal virion proteins found in the retroviral genome. . J Virol. 2003;77:6305-13. (6.) Farina SF, Gao GP, Xiang ZQ, Rux JJ, Burnett RM, Alvira MR, et al. Replication-defective vector based on a chimpanzee adenovirus. J Virol. 2001;75:11603-13. (7.) Shiver JW. Gene therapy: chimpanzee-origin adenovirus vectors as vaccine. Banff, Alberta Banff is the largest town in Banff National Park, located in Alberta's Rockies, Canada. At m ( ft), it is the town with the highest elevation in Canada, situated above Bow Falls near the junction of the Bow and Spray Rivers. , Canada: Keystone Symposia; 2003. (8.) Basnight M Jr, Rogers NG, Gibbs CJ Jr, Gajdusek DC. Characterization of four new adenovirus serotypes isolated from chimpanzee tissue explants. Am J Epidemiol. 1971;94:166-71. (9.) The LOGISTIC procedure. SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. version 9.1.3. Cary (NC): SAS Institute SAS Institute Inc., headquartered in Cary, North Carolina, USA, has been a major producer of software since it was founded in 1976 by Anthony Barr, James Goodnight, John Sall and Jane Helwig. , Inc.; 2005. (10.) Reyes-Sandoval A, Fitzgerald JC, Grant R, Roy S, Xiang ZQ, Li Y, et al. Human immunodeficiency virus type 1-specific immune responses in primates upon sequential immunization immunization: see immunity; vaccination. with adenoviral vaccine carriers of human and simian serotypes. J Virol. 2004;78:7392-9. (11.) Tutin CE. Ecology and social organization of African tropical forest primates: aid in understanding retrovirus transmission. Bull Soc Pathol Exot. 2000;93:157-61. (12.) Hahn BH, Shaw GM, De Cock KM, Sharp PM. AIDS as a zoonosis Zoonosis Definition Zoonosis, also called zoonotic disease refers to diseases that can be passed from animals, whether wild or domesticated, to humans. : scientific and public health implications. Science. 2000;287:607-14. (13.) Switzer WM, Bhullar V, Shanmugam V, Cong M, Parekh B, Lerche NW, et al. Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates. J Virol. 2004;78:2780-9. (14.) Calattini S, Maudere P, Tortevoye P, Froment A, Saib A, Gessain A. Interspecies transmission of simian foamy virus from chimpanzees and gorillas to Bantus and Pygmy hunters in southern Cameroon [abstract]. Wurzburg, Germany: Fifth International Foamy Virus foam·y virus n. Any of the various retroviruses found in primates and other mammals and characterized by the lacelike changes they cause in monkey kidney cells. Conference. 2004 Jul 9-11. (15.) Kostense S, Koudstaal W, Sprangers M, Weverling GJ, Penders G, Helmus N, et al. Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector. AIDS. 2004;18:1213-6. Address for correspondence: Hildegund C.J. Ertl, The Wistar Institute The Wistar Institute, an independent nonprofit biomedical research institute in Philadelphia, Pennsylvania, United States, is dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. , 3601 Spruce St, Philadelphia, PA 19104, USA; email: ertl@ wistar.upenn.ed The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. or the institutions with which the authors are affiliated. Zhiquan Xiang, * Yan Li, * Ann Cun, * Wei Yang, ([dagger]) Susan Ellenberg, ([dagger]) William M. Switzer, ([double dagger double dagger n. A reference mark (  ) used in printing and writing. Also called diesis.Noun 1. ]) Marcia L. Kalish, ([double dagger]) and Hildegund C.J. Ertl * * The Wistar Institute, Philadelphia, Pennsylvania, USA; ([dagger]) University of Pennsylvania School of Medicine The University of Pennsylvania's School of Medicine, presently located in the University City section of Philadelphia, Pennsylvania, was the United States's first school of medicine, founded at the College of Philadelphia, as the University was then called. , Philadelphia, Pennsylvania, USA; and ([double dagger]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA Dr Xiang is a senior staff scientist at the Wistar Institute. His primary research interests are assessing immune responses to novel vaccine prototypes based on viral vectors and studying immune responses to vaccines expressing antigens of rabies virus rabies virus n. A rather large, bullet-shaped virus of the genus Lyssavirus that causes rabies. or HIV-1.
Table 1. Sera with neutralizing activity to different human and
chimpanzee adenoviruses
% positive samples (p values) *
([dagger])
Origin AdHu5 AdC68
Human controls, United States
(n = 50) 34.0 2.0
Human zoo workers, United States
(n = 50) 28.0 0
Humans, Thailand (n = 200) 76.5 1.5
Humans, Cameroon (n = 405) 55.8 1.7 (0.6764)
Humans, Cote d'Ivoire (n = 169) 95.8 9.5 (0.0003)
Humans, Nigeria (n = 182) 89.0 4.9 (0.0267)
Chimpanzees United States (n = 50) 44.0 86.0 (<0.0001)
% positive samples (p values) *
([dagger])
Origin AdC6 AdC1
Human controls, United States
(n = 50) 4.0 2.0
Human zoo workers, United States
(n = 50) 0 0.0
Humans, Thailand (n = 200) 3.0 4.0
Humans, Cameroon (n = 405) 7.9 (0.0045) 5.4 (0.1248)
Humans, Cote d'Ivoire (n = 169) 10.7 (0.0008) 3.0 (0.9796)
Humans, Nigeria (n = 182) 18.7 (<0.0001) 9.3 (0.0045)
Chimpanzees United States (n = 50) 92.0 (<0.0001) 46.0 (<0.0001)
* p values show statistical difference between percentages of sera
positive for neutralizing antibodies to human and chimpanzee
adenoviruses. Reactivity of human sera from Cameroon. Cote d'Ivoire,
and Nigeria and of chimpanzee sera to the 3 chimpanzee-derived
adenoviruses were compared with human sera from the United States
(n = 100) and Thailand (n = 200); the last 2 were combined because
these countries do not offer natural chimpanzee habitats (similarity of
USA and Thailand data for these adenoviruses was statistically
confirmed). A logistic regression model was fitted to percentages of
samples positive for neutralizing antibodies between different groups.
A p value <0.05 was considered statistically significant. All analyses
were performed by using SAS version 9.1 logistic procedure (9).
([dagger]) Virus tested for neutralization with a previously described
neutralization assay (10). Samples that neutralized virus at dilutions
[greater than or equal to] 1:20 were scored as positive.
Table 2. Mean adenovirus neutralizing antibody titers for positive
samples
Mean VNA * titer [+ or -] standard
deviation ([dagger])
Origin AdHu5
Humans, United States 116 [+ or -] 111#
Humans, Thailand 303 [+ or -] 353 ([double dagger])#
Humans, Cameroon 125 [+ or -] 114#
Humans, Cote d'Ivoire 162 [+ or -] 212#
Humans, Nigeria 165 [+ or -] 206#
Chimpanzees, United States 164 [+ or -] 233#
Mean VNA * titer [+ or -] standard
deviation ([dagger])
Origin AdC68
Humans, United States 40 [+ or -] 0
Humans, Thailand 20 [+ or -] 0
Humans, Cameroon 109 [+ or -] 145
Humans, Cote d'Ivoire 60 [+ or -] 51# ([double dagger])
Humans, Nigeria 29 [+ or -] 20
Chimpanzees, United States 201 [+ or -] 204#
Mean VNA * titer [+ or -] standard
deviation ([dagger])
Origin AdC6
Humans, United States 20 [+ or -] 0
Humans, Thailand 80 [+ or -] 44
Humans, Cameroon 82 [+ or -] 52 ([double dagger])#
Humans, Cote d'Ivoire 37 [+ or -] 34 ([double dagger])#
Humans, Nigeria 80 [+ or -] 115 ([double dagger])#
Chimpanzees, United States 137 [+ or -] 160#
Mean VNA * titer [+ or -] standard
deviation ([dagger])
Origin AdC1
Humans, United States 20 [+ or -] 0
Humans, Thailand 33 [+ or -] 25#
Humans, Cameroon 58 [+ or -] 41#
Humans, Cote d'Ivoire 148 [+ or -] 275
Humans, Nigeria 42 [+ or -] 23#
Chimpanzees, United States 64 [+ or -] 72#
Note: Experimental samples in which [greater than or equal to] 10
samples were positive for the given adenovirus are indicated with #.
* VNA , virus neutralizing antibody.
([dagger]) p values were determined by a Student t test to assess
differences between titers in experimental samples and control samples.
Human sera from the United States were used as a reference for
antibodies to AdHu5, and chimpanzee sera were used as a reference for
titers to AdC68, AdC6, and AdC1. Experimental samples in which
[greater than or equal to] 10 samples were positive for the given
adenovirus are shown in boldface.
([double dagger]) Samples that showed a statistically significant
difference (p<0.05).
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