A large-scale population-based study reveals that gp42-IgG antibody is protective against EBV-associated nasopharyngeal carcinoma

Abstract

BACKGROUNDEBV is associated with nasopharyngeal carcinoma (NPC), but the existence of a NPC protective antibody against EBV-associated antigens remains unclear.METHODSPatients with NPC and matched controls were identified from prospective cohorts comprising 75,481 participants in southern China. ELISA and conditional logistic regression were applied to assess the effects of gp42-IgG on NPC. The expression of HLA-II, the gp42 receptor, in nasopharyngeal atypical dysplasia and its effect on EBV infection of epithelial cells were evaluated.FINDINGSgp42-IgG titers were significantly lower in patients with NPC compared with controls across various follow-up years before NPC diagnosis (P < 0.05). Individuals in the highest quartile for gp42-IgG titers had a 71% NPC risk reduction compared with those in the lowest quartile (ORsQ4vsQ1= 0.29, 95% CIs = 0·15 to 0.55, P < 0.001). Each unit antibody titer increase was associated with a 34% lower risk of NPC (OR = 0.66, 95% CI = 0.54-0.81, Ptrend< 0.001). The protective effect of of gp42-IgG was observed in patients diagnosed 5 years or more, 1-5 years, and less than 1 year after blood collection (P < 0.05). HLA-II expression was detected in 13 of 27 specimens of nasopharyngeal atypical dysplasia, and its overexpression substantially promoted epithelial cell-origin EBV infection.CONCLUSIONElevated EBV gp42-IgG titers can reduce NPC risk, indicating that gp42 is a potential EBV prophylactic vaccine target.TRIAL REGISTRATIONNCT00941538, NCT02501980, ChiCTR2000028776, ChiCTR2100041628.FUNDINGNoncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501003), National Natural Science Foundation of China (82030046, 82073625, 81860601, 82373655), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2019BT02Y198), and Central Financial Transfer Payment Projects of the Chinese Government, Cancer Research Grant of Zhongshan City.

Keywords: Antigen; Epidemiology; Head and neck cancer; Vaccines; Virology.

Figure 1. A Flow chart of the study design.

A total 75,481 individuals from 3 independent prospective cohorts established in 3 NPC epidemic regions (Sihui city, Guangdong Province; Wuzhou city, Guangxi Province; Zhongshan city, Guangdong Province) in southern China were recruited from the years 2014 to 2018, 2018 to 2021, and 2012, respectively. A total of 129 serum-available incident NPC cases were identified until 2023, and each patient was matched to 3 controls from individual cohort by age, sex, and sample collection dates. Titers of gp42-IgG, VCA-IgA, and EBNA1-IgA were measured by ELISA.

Figure 2. Analysis of gp42-IgG levels in the nested case control study.

Distributions of gp42-IgG levels in (A) the overall cohort, (B) the cohort with a follow-up duration of 1 year or less, (C) the cohort with a follow-up duration of 1–5 years, and (D) the cohort with follow-up duration 5 or more years. rOD is a standardized OD₄₅₀ – OD₆₃₀ value, which was consistent across testing batches (see Methods for details). The lines at the top of each histogram represent kernel density estimations. The Wilcoxon test was used to calculate P values, which are shown under the subtitles. Numbers in parentheses in the legends refer to the number of participants in each group.

Figure 3. HLA-II expression in nasopharyngeal atypical dysplasia.

(A and D) H&E stained images. (B and E) ISH was performed to detect EBERs. (C and F) IHC was performed to detect HLA-DRA. The sample shown is representative of 27 samples. Original magnification, ×20 (A–C). Images in D–F were zoomed in from the black outlined regions; scale bars: 50 μm.