International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations

Abstract

Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4 × 10¹⁰ vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.

Introduction

A limitation that has become apparent with rAd5 vaccine vectors is the high titers of Ad5 NAbs in human populations, particularly in the developing world. Baseline Ad5 NAbs have been shown to suppress the immunogenicity of rAd5 vector-based vaccines for HIV-1 in both preclinical studies [1], [2] and clinical trials [3], [4], [5], although higher doses of rAd5 vectors can partially overcome this effect. To address this and other problems with rAd5 vectors, alternative human serotype rAd vectors [6], [7], [8], hexon-chimeric rAd vectors [2], and rAd vectors derived from other species [9], [10] have been constructed.

In particular, rAd26 and rAd35 vectors are currently being evaluated in phase 1 HIV-1 vaccine clinical trials in both the United States and sub-Saharan Africa. Ad26 (subgroup D), Ad35 (subgroup B), and Ad48 (subgroup D) are derived from different Ad subgroups than Ad5 (subgroup C). Moreover, these alternative Ad serotypes differ from Ad5 in terms of their receptor usage [6], [8], tropism [11], dendritic cell stimulatory capacity [12], innate immune profile (D.H.B., unpublished data), adaptive immune phenotype [13], and capacity to protect against SIV challenge in rhesus monkeys [14].

Building on Ad seroepidemiology studies previously reported from our laboratory and others [6], [8], [15], [16], [17], [18], [19], we report here a large study of Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 pediatric and adult subjects from North America, South America, sub-Saharan Africa, and Southeast Asia. We also model the impact of typical Ad26 NAb titers found in the developing world on rAd26 vaccine immunogenicity in a pilot study in rhesus monkeys.