{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:56:42Z","timestamp":1753891002944,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no \u2018empirical\u2019 evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin\/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. <jats:italic>In vivo<\/jats:italic> impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgG<jats:sub>Sp<\/jats:sub>) in serum were assessed in Balb\/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgG<jats:sub>Sp<\/jats:sub> levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV as well as in 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV. Higher Co-mV concentrations and transient drug holidays were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed significantly lower IgG<jats:sub>SP<\/jats:sub> response in IC patients (p&amp;lt;0.0001) compared to their matched controls in 2D and 3D Co-mV groups. IC patients on M or S showed a profound dampening of IgG<jats:sub>SP<\/jats:sub> response relative to those that were not on these drugs. M and S, when used individually or in combination, significantly attenuated the Co-mV-induced Sp expression, whereas T did not exert significant influence. Sirolimus combo pretreatment <jats:italic>in vivo<\/jats:italic> significantly attenuated the Co-mV induced IgM<jats:sub>Sp<\/jats:sub> and IgG<jats:sub>Sp<\/jats:sub> production, which correlated with a decreasing trend in the early levels (after day 1) of Co-mV induced Sp immunogen levels. Neither higher Co-mV concentrations (6\u03bcg) nor withholding S for 1-day could overcome the inhibition of Sp protein levels. Interestingly, 3-days S holiday or using T alone rescued Sp levels <jats:italic>in vitro.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis <jats:italic>via<\/jats:italic> translation repression. Selective use of tacrolimus or drug holiday of sirolimus can be a potential means to rescue translation-dependent Sp protein production. These findings lay a strong foundation for guiding future studies aimed at improving Co-mV responses in high-risk IC patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1020165","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T10:05:51Z","timestamp":1666778751000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Translation suppression underlies the restrained COVID-19 mRNA vaccine response in the high-risk immunocompromised group"],"prefix":"10.3389","volume":"13","author":[{"given":"Kangsan","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhusudhanan","family":"Narasimhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lenin","family":"Mahimainathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ray","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Araj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Tharpe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin M.","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan-Zhen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-An","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravi","family":"Sarode","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivas","family":"Malladi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alagarraju","family":"Muthukumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines9070708","article-title":"Serological response in lung transplant recipients after two doses of SARS-CoV-2 mRNA vaccines","volume":"9","author":"Narasimhan","year":"2021","journal-title":"Vaccines"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.7489","article-title":"Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients","volume":"325","author":"Boyarsky","year":"2021","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","first-page":"108021","DOI":"10.1016\/j.intimp.2021.108021","article-title":"Administration of COVID-19 vaccines in immunocompromised patients","volume":"99","author":"Negahdaripour","year":"2021","journal-title":"Int Immunopharmacol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05397-7","article-title":"Preliminary evidence of blunted humoral response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients treated with ocrelizumab","volume":"42","author":"Gallo","year":"2021","journal-title":"Neurol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(21)00197-6","article-title":"Blunted humoral response after mRNA vaccine in patients with haematological malignancies","volume":"8","author":"Kamboj","year":"2021","journal-title":"Lancet Haematol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.7326\/M21-1757","article-title":"Effect of immunosuppression on the immunogenicity of mrna vaccines to SARS-CoV-2: A prospective cohort study","volume":"174","author":"Deepak","year":"2021","journal-title":"Ann Intern Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/art.39480","article-title":"2015 American College of rheumatology guideline for the treatment of rheumatoid arthritis","volume":"68","author":"Singh","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/acr.23789","article-title":"Special article: 2018 American college of Rheumatology\/National psoriasis foundation guideline for the treatment of psoriatic arthritis","volume":"71","author":"Singh","year":"2019","journal-title":"Arthritis Care Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1002\/acr.21664","article-title":"American College of rheumatology. 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