Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines

• 成果类型: Article
• 署名作者: Liang, Chieh-Yu; Raju, Saravanan; Liu, Zhuoming; Li, Yuhao; Arunkumar, Guha Asthagiri; Case, James Brett; Scheaffer, Suzanne M.; Zost, Seth J.; Acreman, Cory M.; Gagne, Matthew; Andrew, Shayne F.; dos Anjos, Deborah Carolina Carvalho; Foulds, Kathryn E.; McLellan, Jason S.; Crowe Jr, James E.; Douek, Daniel C.; Whelan, Sean P. J.; Elbashir, Sayda M.; Edwards, Darin K.; Diamond, Michael S.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Vanderbilt University; Vanderbilt University; University of Texas System; University of Texas Austin; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Vanderbilt University; Washington University (WUSTL); Washington University (WUSTL)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6168
• DOI: 10.1038/s41586-024-07539-1
• 发表日期: 2024-06-27
• 关键词: sars-cov-2; replication; domain; cdna

摘要

Immune imprinting is a phenomenon in which prior antigenic experiences influence responses to subsequent infection or vaccination1,2. The effects of immune imprinting on serum antibody responses after boosting with variant-matched SARS-CoV-2 vaccines remain uncertain. Here we characterized the serum antibody responses after mRNA vaccine boosting of mice and human clinical trial participants. In mice, a single dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike protein minimally imprinted serum responses elicited by Omicron boosters, enabling generation of type-specific antibodies. However, imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron vaccine. In both SARS-CoV-2-infected and uninfected humans who received two Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with Omicron variants as well as more distantly related sarbecoviruses. Because serum neutralizing responses against Omicron strains and other sarbecoviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series. Thus, the antibody response to Omicron-based boosters in humans is imprinted by immunizations with historical mRNA-1273 vaccines, but this outcome may be beneficial as it drives expansion of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and distantly related sarbecoviruses. In mouse experiments and in clinical trials in humans, boosting with Omicron-specific mRNA following immunization with Wuhan-1 spike mRNA results in immune responses focused on conserved rather than variant-specific epitopes.