Hertz T, Logan M G, Rolland M, Magaret C A, Rademeyer C, Fiore-Gartland A, Edlefsen P T, DeCamp A, Ahmed H, Ngandu N, Larsen B B, Frahm N, Marais J, Thebus R, Geraghty D, Hural J, Corey L, Kublin J, Gray G, McElrath M J, Mullins J I, Gilbert P B, Williamson C
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
Division of Medical Virology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town 7925, South Africa.
Vaccine. 2016 Nov 11;34(47):5792-5801. doi: 10.1016/j.vaccine.2016.09.054. Epub 2016 Oct 15.
The Merck Adenovirus-5 Gag/Pol/Nef HIV-1 subtype-B vaccine evaluated in predominately subtype B epidemic regions (Step Study), while not preventing infection, exerted vaccine-induced immune pressure on HIV-1 breakthrough infections. Here we investigated if the same vaccine exerted immune pressure when tested in the Phambili Phase 2b study in a subtype C epidemic.
A sieve analysis, which compares breakthrough viruses from placebo and vaccine arms, was performed on 277 near full-length genomes generated from 23 vaccine and 20 placebo recipients. Vaccine coverage was estimated by computing the percentage of 9-mers that were exact matches to the vaccine insert.
There was significantly greater protein distances from the vaccine immunogen sequence in Gag (p=0.045) and Nef (p=0.021) in viruses infecting vaccine recipients compared to placebo recipients. Twenty-seven putative sites of vaccine-induced pressure were identified (p<0.05) in Gag (n=10), Pol (n=7) and Nef (n=10), although they did not remain significant after adjustment for multiple comparisons. We found the epitope sieve effect in Step was driven by HLA A∗02:01; an allele which was found in low frequency in Phambili participants compared to Step participants. Furthermore, the coverage of the vaccine against subtype C Phambili viruses was 31%, 46% and 14% for Gag, Pol and Nef, respectively, compared to subtype B Step virus coverage of 56%, 61% and 26%, respectively.
This study presents evidence of sieve effects in Gag and Nef; however could not confirm effects on specific amino acid sites. We propose that this weaker signal of vaccine immune pressure detected in the Phambili study compared to the Step study may have been influenced by differences in host genetics (HLA allele frequency) and reduced impact of vaccine-induced immune responses due to mismatch between the viral subtype in the vaccine and infecting subtypes.
默克腺病毒5型Gag/Pol/Nef HIV-1 B亚型疫苗在主要为B亚型流行地区进行评估（STEP研究），虽然未能预防感染，但对HIV-1突破性感染施加了疫苗诱导的免疫压力。在此，我们调查了在C亚型流行地区进行的Phambili 2b期研究中测试该疫苗时是否也施加了免疫压力。
对来自23名疫苗接种者和20名安慰剂接受者的277个近乎全长的基因组进行筛选分析，比较安慰剂组和疫苗组的突破性病毒。通过计算与疫苗插入片段完全匹配的9聚体的百分比来估计疫苗覆盖率。
与安慰剂接受者相比，感染疫苗接种者的病毒在Gag（p = 0.045）和Nef（p = 0.021）中与疫苗免疫原序列的蛋白距离显著更大。在Gag（n = 10）、Pol（n = 7）和Nef（n = 10）中确定了27个假定的疫苗诱导压力位点（p < 0.05），尽管在进行多重比较调整后它们不再显著。我们发现STEP研究中的表位筛选效应是由HLA A∗02:01驱动的；与STEP参与者相比，该等位基因在Phambili参与者中的频率较低。此外，疫苗对C亚型Phambili病毒的Gag、Pol和Nef的覆盖率分别为31%、46%和14%，而对B亚型STEP病毒的覆盖率分别为56%、61%和26%。
本研究提供了Gag和Nef中筛选效应的证据；然而，未能证实对特定氨基酸位点的影响。我们提出Phambili研究中检测到的疫苗免疫压力信号比STEP研究中弱，这可能受到宿主遗传学差异（HLA等位基因频率）以及疫苗中病毒亚型与感染亚型不匹配导致疫苗诱导免疫反应影响降低的影响。
