Epidemiology of adenovirus type 5 neutralizing antibodies in healthy people and AIDS patients in Guangzhou, southern China

doi:10.1016/j.vaccine.2011.03.042

Vaccine

Volume 29, Issue 22, 17 May 2011, Pages 3837-3841

https://doi.org/10.1016/j.vaccine.2011.03.042 Get rights and content

Abstract

Recombinant adenovirus serotype 5 (Ad5) viruses have been extensively explored as vectors for vaccination or gene therapy. However, one major obstacle to their clinical application is the high prevalence of preexisting anti-Ad5 immunity resulting from natural infection. It has been reported that there are geographic variations in the prevalence of natural adenovirus infection. In the present study, we investigated the seroprevalence of Ad5 in Guangzhou, southern China by measuring the Ad5 neutralizing antibodies in blood samples collected from several sites. The seroprevalence was 77.34% in the general healthy population. The seroprevalence and antibody titers increased with age, with the older population (41-72 years old) having the highest seropositivity (84.8%) and percentage (54.4%) of high Ad5 neutralizing antibody titers (>1000). The dynamics of Ad5 neutralizing antibodies were stable and persistent over the course of eight months. Furthermore, the seroprevalence of Ad5 in the HIV-infected AIDS patients was investigated and there was no significant difference from the general healthy population. Our survey provides useful insights for the future development of Ad5-based vaccination and gene therapy.

Section snippets

Background

Recombinant adenoviruses, especially replication-defective adenovirus serotype 5 (Ad5), have been extensively explored as vectors for gene therapy or vaccines against human immunodeficiency virus (HIV), hepatitis virus, influenza virus, other infectious diseases and cancers [1], [2], [3], [4]. However, the practical application of Ad5 has been potentially limited by the high prevalence of preexisting anti-Ad5 immunity. Both preclinical animal models and human clinical trials have demonstrated

Human samples

Serum samples were isolated from 278 healthy participants and 32 HIV-infected AIDS patients in Guangzhou, Guangdong province, southern China. The participants’ ages ranged from 6 to 72 years old, and the sex ratio was approximately 1:1 (male:female = 51.8%:48.2%). The samples from healthy participants were collected from the Guangzhou Center for Disease Control and Prevention (CDC), Guangzhou Children's Hospital, and Guangzhou Institute of Biomedicine and Health (GIBH), and the samples from

Confirmation of Ad5 neutralizing antibody titers by western blot analyses

To confirm whether the titers calculated using the above methods Ad5 neutralizing assay were correlated with the actual statuses of pre-existing antibodies specifically recognizing Ad5 proteins, samples with different titers (<18, 18–200, 200–1000, >1000) of Ad5 neutralizing antibodies were analyzed by western blot analyses. As shown in Fig. 1, the results obtained by those two methods are concurrent with each other. The sera with the highest Ad5 neutralizing antibodies titer (>1,000) had the

Discussion

Human adenovirus type 5 belongs to the mastadenovirus family in the order of adenoviridae, and is a non-segmented, double stranded, non-enveloped DNA virus. Recombinant Ad5 has been extensively exploited as a gene delivery vehicle for vaccination and gene therapy attributing to its relatively well understood biology: good safety record from many clinical trials, no integration into the host genome, ability to infect a variety of cell types, and capable of production in high yield and titer.

Acknowledgements

This study was supported by the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX1-YW-10, KSCX2-EW-J-27), the National Key Science & Technology Specific Projects of China (2008ZX10001-011), the National Natural Science Foundation of China (81000737), and the National Science Fund for Distinguished Young Scholars of China (No.30688004). We gratefully acknowledge Yichu Liu and Xuehua Zheng for their technical supports.

References (23)

C. Sun et al.
Induction of balance and breadth in the immune response is beneficial for the control of SIVmac239 replication in rhesus monkeys
J Infect
(2010)
T.C. Mast et al.
International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials
Vaccine
(2010)
S.P. Buchbinder et al.
Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial
Lancet
(2008)
M.J. McElrath et al.
HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis
Lancet
(2008)
J.T. Douglas
Adenoviral vectors for gene therapy
Mol Biotechnol
(2007)
J.W. Shiver et al.
Replication-defective adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity
Nature
(2002)
J. Liu et al.
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys
Nature
(2009)
S.M. Sumida et al.
Neutralizing antibodies and CD8+ T lymphocytes both contribute to immunity to adenovirus serotype 5 vaccine vectors
J Virol
(2004)
S.L. Pichla-Gollon et al.
Effect of preexisting immunity on an adenovirus vaccine vector: in vitro neutralization assays fail to predict inhibition by antiviral antibody in vivo
J Virol
(2009)
K.L. Molnar-Kimber et al.
Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma
Hum Gene Ther
(1998)

E. Nwanegbo et al.

Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia South Africa, and the United States

Clin Diagn Lab Immunol

(2004)

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Short communicationEpidemiology of adenovirus type 5 neutralizing antibodies in healthy people and AIDS patients in Guangzhou, southern China

Abstract

Section snippets

Background

Human samples

Confirmation of Ad5 neutralizing antibody titers by western blot analyses

Discussion

Acknowledgements

J Infect

Vaccine

Lancet

Lancet

Adenoviral vectors for gene therapy

Mol Biotechnol

Replication-defective adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity

Nature

Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys

Nature

Neutralizing antibodies and CD8+ T lymphocytes both contribute to immunity to adenovirus serotype 5 vaccine vectors

J Virol

Effect of preexisting immunity on an adenovirus vaccine vector: in vitro neutralization assays fail to predict inhibition by antiviral antibody in vivo

J Virol

Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma

Hum Gene Ther

Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia South Africa, and the United States

Clin Diagn Lab Immunol

Short communication
Epidemiology of adenovirus type 5 neutralizing antibodies in healthy people and AIDS patients in Guangzhou, southern China