帶有HBsAg疫苗逃逸突變的HBV複雜譜的起義循環

StephenW

Uprising circulation of HBV-complex profiles with HBsAg vaccine-escape mutations

Complex Vaccine-Escape Mutation Profiles in 947 People With HBV

CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021

Mark Mascolini

Complex vaccine-escape mutational profiles appeared in a substantial fraction of 947 HBV genotype D patients seen from 2005 through 2019 at the University of Rome “Tor Vergata” [1]. Emergence of these complex mutational profiles rose over time and correlated with lower hepatitis B surface antigen (HBsAg) levels and with HBsAg negativity despite ongoing HBV replication. The Tor Vergata investigators believe their findings could have implications for development of new HBV vaccines.

Anti-HBV antibodies target the major hydrophilic region of HBsAg, explained the researchers who conducted this study. Escape mutations affect the major hydrophilic region and thus can impair vaccine efficacy as well as HBsAg detection by immunoassays. Both of these changes clearly can affect prevention and management of HBV infection. In the United State HBV vaccination is recommended for any adult at risk for HBV infection, which includes a long list of groups briefly summarized below [2].

The University of Rome team studied their HBV population to assess (1) changing prevalence of vaccine-escape mutations over time, (2) evidence of complex mutational profiles, and (3) the impact of these mutations in a large group with HBV genotype D. Genotype D predominates in Europe, A in the United States, C in the Far East, and B in Southeast Asia [3]. But genotype D virus also appears in the United States, Canada, North Africa, and the region stretching from Turkey to India [4].

The study focused on 947 viremic people with HBV genotype D infection seen in routine practice at Tor Vergota University Hospital from 2005 through 2019. In viral samples from all 947 people, the investigators sequenced the HBsAg region (amino acids 1-226) by population sequencing. The researchers considered 21 HBsAg vaccine-escape mutations at 12 HBsAg major hydrophilic region positions. They defined a complex mutational profile as one with 2 or more escape mutations.

Two thirds of the study group (64.7%) were men, median age stood at 57 (interquartile range [IQR] 44 to 68), and 73.8% were Italian in nationality. Median year of sample collection was 2013 (IQR 2010-2015).

Almost 1 in 5 participants, 17.8%, had 1 or more vaccine-escape mutations, 14.7% had just 1 escape mutation, and 3.1% had a complex mutational profile. Subgenotype D3 had a higher prevalence of vaccine-escape mutations (22.9%) than subgenotypes D9 (15.4%), D2 (14.7%),  D7 (14.3%), or D1 (13.4%) (P < 0.001). The most frequent individual escape mutations were P120S (21.4%), T131N (15.5%), and D144E (13.1%).

Prevalence of complex mutational profiles rose significantly over time, from 0.4% in 2005-2009, to 3.0% in 2010-2014, and to 5.1% in 2015-2019 (P = 0.007). The researchers believe this finding underlines the need to get a better understanding of how vaccination strategies favor selection of complex mutational profiles.

Presence of complex mutational profiles correlated with lower HBsAg levels, and that finding suggests these profiles may affect HBsAg quantification. Presence of complex mutational profiles of vaccine-escape mutations also correlated with HBsAg negativity despite ongoing HBV replication. In fact, 35% of people with complex mutational profiles tested negative for HBsAg, a finding supporting the conclusion that presence of more viral escape mutations can affect HBsAg detection. The researchers also found that complex mutational profiles containing the T126I/A mutation occur often in HBsAg-negative people.

The Tor Vergata investigators concluded that vaccine-escape mutations and complex mutational profiles appear in a considerable fraction of people with genotype D HBV. And prevalence of complex mutational profiles has grown over time. They argued that these mutations “should be considered for a proper clinical interpretation of HBsAg results.” And they believe circulation of these mutations should inform development of novel HBV vaccines that target epitopes outside the major hydrophilic region, such as the Pre-S1 and Pre-S2 regions.

References
1. Piermatteo L, Alkhatib M, Bertoli A, et al. Uprising circulation of HBV-complex profiles with HBsAg vaccine-escape mutations. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 137.
2. Centers for Disease Control and Prevention. Hepatitis B vaccination of adults. https://www.cdc.gov/hepatitis/hbv/vaccadults.htm. HBV vaccine candidates include men who have sex with men; sexually active people not in a long-term mutual monogamous relationship; people seeking evaluation or treatment of a sexually transmitted infection; current or recent injection-drug users; sex partners of HBsAg-positive people; people with HIV, HCV, chronic liver disease, or diabetes (ages 19-59); and more.
3. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125:444-451. doi: 10.1016/s0016-5085(03)00895-3.
4. Al-Sadeq DW, Taleb SA, Zaied  RE, et al. Hepatitis B virus molecular epidemiology, host-virus interaction, coinfection, and laboratory diagnosis in the MENA region: an update. Pathogens. 2019;8(2):63. doi: 10.3390/pathogens8020063.

StephenW

帶有HBsAg疫苗逃逸突變的HBV複雜譜的起義循環

947名乙肝患者的複雜疫苗逃逸突變譜

CROI 2021，逆轉錄病毒和機會感染會議，2021年3月6日至10日

馬克·馬斯科利尼

從2005年至2019年，羅馬大學“ Tor Vergata”分校的947名HBV基因型D患者中，相當一部分出現了逃避疫苗的複雜突變現象[1]。這些複雜的突變譜的出現隨著時間的推移而上升，並且儘管正在進行HBV複製，但與較低的乙型肝炎表面抗原（HBsAg）水平和HBsAg陰性相關。 Tor Vergata研究人員認為，他們的發現可能對開發新的HBV疫苗有影響。

進行這項研究的研究人員解釋說，抗HBV抗體靶向HBsAg的主要親水區域。逃逸突變會影響主要的親水區域，因此會削弱疫苗效力以及通過免疫測定法檢測HBsAg的能力。這兩個變化顯然都可以影響對HBV感染的預防和管理。在美國，建議對有HBV感染風險的任何成年人進行HBV疫苗接種，其中包括一長列的小組，簡述如下[2]。

羅馬大學小組研究了他們的HBV人群，以評估（1）隨著時間的推移，疫苗逃逸突變的流行率不斷變化，（2）複雜突變譜的證據，以及（3）這些突變對具有D型HBV基因的大型人群的影響基因型D在歐洲占主導地位，美國為A，遠東為C，東南亞為B [3]。但是基因型D病毒也出現在美國，加拿大，北非以及從土耳其延伸到印度的地區[4]。

該研究集中於2005年至2019年在Tor Vergota大學醫院的常規實踐中觀察到的947例HBV基因型D型感染的病毒血症人群。在所有947例人群的病毒樣本中，研究人員通過人群測序對HBsAg區（1-226位氨基酸）進行了測序。 。研究人員考慮了在12個HBsAg主要親水區域的21個HBsAg疫苗逃逸突變。他們將復雜的突變譜定義為具有兩個或多個逃逸突變的突變譜。

研究組的三分之二（64.7％）是男性，中位年齡為57歲（四分位間距[IQR] 44至68），意大利裔佔73.8％。樣本收集的中位數是2013（IQR 2010-2015）。

五分之一的參與者（17.8％）具有1個或多個疫苗逃逸突變，14.7％僅有1個逃逸突變，3.1％具有復雜的突變特徵。亞基因型D3的疫苗逃避突變發生率（22.9％）高於亞基因型D9（15.4％），D2（14.7％），D7（14.3％）或D1（13.4％）（P <0.001）。最常見的個體逃逸突變為P120S（21.4％），T131N（15.5％）和D144E（13.1％）。

隨著時間的推移，複雜突變譜的流行率顯著上升，從2005-2009年的0.4％，上升到2010-2014年的3.0％，以及2015-2019年的5.1％（P = 0.007）。研究人員認為，這一發現強調需要更好地了解疫苗接種策略如何有利於選擇複雜的突變譜。

複雜突變譜的存在與較低的HBsAg水平相關，該發現表明這些譜可能會影響HBsAg的定量。儘管正在進行HBV複製，但疫苗逃逸突變的複雜突變譜的存在也與HBsAg陰性相關。實際上，有35％的具有復雜突變特徵的人的HBsAg呈陰性，這一發現支持以下結論：更多病毒逃逸突變的存在會影響HBsAg的檢測。研究人員還發現，在HBsAg陰性人群中經常會出現包含T126I / A突變的複雜突變譜。

Tor Vergata研究人員得出結論，在相當一部分D型HBV基因型患者中出現了疫苗逃逸突變和復雜的突變情況。隨著時間的流逝，複雜的突變譜的流行率也在增長。他們認為，這些突變“應被視為對HBsAg結果的正確臨床解釋。”他們認為，這些突變的流通將為新型HBV疫苗的開發提供信息，這些疫苗靶向主要親水區域（如Pre-S1和Pre-S2）之外的表位。

參考
1. Piermatteo L，Alkhatib M，Bertoli A等。帶有HBsAg疫苗逃逸突變的HBV複雜譜的起義循環。 CROI 2021，逆轉錄病毒和機會感染會議，2021年3月6日至10日，摘要137。
2.疾病預防控制中心。 成人接種乙肝疫苗。 https://www.cdc.gov/hepatitis/hbv/vaccadults.htm。 乙肝疫苗候選者包括與男性發生性關係的男性； 性活躍的人，不是長期的一夫一妻制關係； 尋求評估或治療性傳播感染的人； 當前或最近的注射毒品使用者； HBsAg陽性人群的性伴侶； HIV，HCV，慢性肝病或糖尿病患者（19-59歲）； 和更多。
3. Chu CJ，Keeffe EB，Han SH等。 美國的乙型肝炎病毒基因型：一項全國性研究的結果。 腸胃病學。 2003; 125：444-451。 doi：10.1016 / s0016-5085（03）00895-3。
4. Al-Sadeq DW，Taleb SA，Zaied RE等。 中東和北非地區的乙型肝炎病毒分子流行病學，宿主-病毒相互作用，合併感染和實驗室診斷：最新情況。 病原體。 2019; 8（2）：63。 doi：10.3390 / pathogens8020063。