Your browser doesn't support javascript.
Translation suppression underlies the restrained COVID-19 mRNA vaccine response in the high-risk immunocompromised group.
Kim, Kangsan; Narasimhan, Madhusudhanan; Mahimainathan, Lenin; Zhang, Ray; Araj, Ellen; Kim, Elizabeth; Tharpe, William; Greenberg, Benjamin M; Greenberg, David E; Li, Quan-Zhen; Cheng, Chi-An; Sarode, Ravi; Malladi, Srinivas; Muthukumar, Alagarraju.
  • Kim K; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Narasimhan M; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Mahimainathan L; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Zhang R; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Araj E; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Kim E; William P. Clements Jr. University Hospital, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Tharpe W; William P. Clements Jr. University Hospital, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Greenberg BM; Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Greenberg DE; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Li QZ; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Cheng CA; Microarray Core, Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Sarode R; School of Pharmacy, National Taiwan University, Taipei, Taiwan.
  • Malladi S; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • Muthukumar A; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States.
Front Immunol ; 13: 1020165, 2022.
Article in English | MEDLINE | ID: covidwho-2114621
ABSTRACT

Background:

Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV. Materials and

methods:

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. In vivo impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgGSp) in serum were assessed in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgGSp 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.

Results:

We observed significantly lower IgGSP response in IC patients (p<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 IgGSP 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 in vivo significantly attenuated the Co-mV induced IgMSp and IgGSp 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 (6µg) 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 in vitro.

Conclusions:

This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis via 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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Vaccines / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Animals / Humans Language: English Journal: Front Immunol Year: 2022 Document Type: Article Affiliation country: Fimmu.2022.1020165

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Vaccines / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Animals / Humans Language: English Journal: Front Immunol Year: 2022 Document Type: Article Affiliation country: Fimmu.2022.1020165