A recent study posted to the medRxiv* preprint server examined the post-coronavirus disease 2019 (COVID-19) state of the immune system after a seasonal influenza vaccine.
Study: Influenza vaccination reveals and partly reverses sex dimorphic immune imprints associated with prior mild COVID-19. Image Credit: Sutthituch/Shutterstock
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Symptoms of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can persist for several months post-infection, known as long COVID or post-COVID-19 syndrome. Long COVID can develop in patients with severe COVID-19 (requiring hospitalization) and those with mild disease during COVID-19.
The information on cellular and molecular changes of the immune system post-COVID-19 recovery is lacking. Given that patients developing the mild disease can also present post-COVID-19 syndrome, it is imperative to understand the changes in the baseline immune states to natural infection and subsequent immune challenges with vaccination. For instance, humoral responses decrease post measles infection, and the individuals become more susceptible to non-measles infection for a few months to several years.
The study
In the present study, researchers used a systems immunology approach to analyze the immune states of healthy and non-obese subjects who recovered from mild COVID-19 (non-hospitalized) and compared them with age- and sex-matched COVID-19-naive controls (healthy controls or HCs).
Besides examining the differences in immune states between the two cohorts, the authors also used influenza vaccination to investigate the immunological states at serological, proteomic, transcriptional, and cellular levels.
Findings
The mean duration between COVID-19 diagnosis and study enrolment was 151 days. COVID-19 diagnosis was confirmed with a polymerase chain reaction (PCR) test for symptomatic cases and antibody tests for asymptomatic individuals. None of the subjects required hospitalization and developed mild COVID-19 disease. All participants were healthy without comorbidities or autoimmune disorders, or obesity. About 12 individuals complained of lingering symptoms (anosmia, ageusia, etc.) at the start of the study, with females being at higher odds of having sequelae.
In line with previous studies, the neutralizing antibody titers of SARS-CoV-2 reduced with an increase in the time since COVID-19 diagnosis (TSD). The red cell distribution width (RDW) that measures the variation of red cell volume had a negative correlation with TSD both in COVID-19-recovered males (COVR-M) and females (COVR-F), indicating hematopoietic disruption even in mild cases. A similar negative correlation with TSD was noted for plasmablast transcriptional signatures in COVR-F (not seen in COVR-M) indicative of sex-specific immune response.
COVR-M showed high frequencies of monocytes and classical dendritic cells (cDCs) equivalent to that in HC females. No sex-specific differences were noted in metabolic transcriptional signatures viz. the mechanistic target of rapamycin complex 1 (mTORC1) signaling and oxidative phosphorylation.
Next, the authors explored the associations of post-COVID-19 immunological states to subsequent non-SARS-CoV-2 immunological challenges. A quadrivalent influenza vaccine was offered to the participants, and their immune responses were investigated at different levels (cellular, molecular and serological) by following them longitudinally for up to 100 days. Patients with lingering symptoms (long COVID) showed adverse effects like pain at the injection site and myalgia following flu vaccination.
Sex-dependent differences were prominent upon vaccination, and COVR-M were high responders to the flu vaccine than HC males. Flu-specific plasmablasts were higher in COVR-M than HC males at day seven. CD71hi memory B lymphocytes, including flu-specific memory B cells within this subpopulation, were higher in COVR-M than HC males before vaccination (higher baseline levels), probably due to broad and non-specific antigen activation of B cells.
COVR-M had greater interferon (IFN) transcriptional signatures on day one after flu vaccination than HC males. After a week of vaccination, natural killer (NK) cell and neutrophil transcriptional patterns were considerably elevated in COVR-F than COVR-M. Moreover, it was observed that the influenza vaccination could boost the transcription of certain innate defense and immune receptor genes of monocytes in COVID-19-recovered subjects that were otherwise depressed before immunization.
Conclusions
The present study evaluated the long-term changes of the immunological states in patients with mild COVID-19 and subsequent immune challenges with the influenza vaccine. It observed that the depressed innate immunity genes in monocytes due to prior mild COVID-19 could return to healthy baseline levels following the initial inflammatory responses against the flu vaccine.
The researchers noted this effect to be more prominent in COVR-F than COVR-M. These findings are consistent with previous reports of sex dimorphic immune responses against SARS-CoV-2. Females who generally respond strongly with acute inflammatory signatures to infections and vaccinations displayed less prominent inflammatory responses to flu vaccination.
COVR-M had more activated immune status at baseline and enhanced innate and adaptive immune responses to the flu vaccine than COVR-F. The observations made in this study hint that a non-SARS-CoV-2 vaccination could reset the immune state created by previous mild COVID-19 to healthy baseline levels.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- Mar 15 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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