Thread by @VirusesImmunity

How does COVID reinfection happen?

Our deep dive into the immune profiles during the 1st and 2nd infections. A case study.

Work led by @sneakyvirus1 @AndersonBrito_ Paul Turbin @peowenlu @BenIsraelow and Marwan Azar (1/)

medrxiv.org/content/10.110…

To address this question, we first looked at other confirmed cases of COVID reinfection. The number of such cases is limited due to the requirement for viral genome sequences in both infections. (2/)

We noted that very little information is available regarding the immune responses that developed during the first infection that can explain why someone would get reinfected. (3/)

We were fortunate to have deep immune profile of a patient who was enrolled in our IMPACT Yale study in March, who became reinfected in November, with 229 days between the first and second infection confirmed by PCR. (4/)

We knew that this was a reinfection and not a lingering viral infection because of negative TMA tests in between, and more importantly, the @NathanGrubaugh team analyzed the viral genomes and found that they belong to distinct lineages. Work of @AndersonBrito_ 💪🏼 (5/)

So why did this patient get reinfected? He is a solid organ transplant recipient who received a number of immunosuppressive drugs. During the 1st infection, he did not suffer from T cells lymphopenia typical of #COVID. Instead, his T cells were mostly exhausted (green dots). (6/)

Between the 1st and 2nd infection, he received rituximab (eliminate circulating B cells) and high dose mycophenolate mofetil (B and T lymphocyte anti-proliferative agent), reducing both B and T cells (orange dot above) 👆🏽Work by @peowenlu (7/)

What about antibodies? The 1st infection induced both IgM and IgG against S1. The second infection only induced IgG not IgM. Typical of a recall response. (8/)

He even developed some neutralizing Abs. However, his NAb response was quite transient and poor in the first infection already declining by day 23. During 2nd infection, there was some NAb response but was very low. Work by @sneakyvirus1 💪🏼 (9/)

Importantly, we found no evidence of immune evasion by the reinfecting viral lineage, as antibody linear epitope mapping by @serimmune showed no overlap in antibody recognition sites and the mutation found in the spike protein (A1078S). (10/)

To distill these data, we found that a solid organ transplant patient was reinfected after 229 days despite having developed some neutralizing antibody. We suspect that his NAb was unable to provide protection because of low levels and potentially poor function. (11/)

The reason he developed such low quality antibody response may be related to the chronic antigen stimulation due to transplant, leading to exhausted T cells and paucity of naive T cells to develop a productive antiviral Tfh response. (12/)

Transplant patients are also impaired in their ability to mount robust Ab immunity after vaccination. A potential use of monoclonal antibody cocktail to prevent/treat this vulnerable group should be considered. (13/)

jamanetwork.com/journals/jama/…

Finally, as always, this was a fantastic collaboration with multiple labs, including @ShelFarFar @NathanGrubaugh @aaronmring and Marwan Azar and all others listed below. #YALEIMPACT (End)