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Complex Vaccine-Escape Mutation Profiles in 947 People With HBV
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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.
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