COVID-19 convalescent plasma (CP) is one of the most studied pharmacological strategies during the pandemic ^{1– 4} . In a recent double-blind, randomized, placebo-controlled trial we showed that early administration of high-titer CP against SARS-CoV-2 to mildly ill infected older adults was a safe therapeutic intervention and reduced the progression to COVID-19 severe respiratory disease (relative risk = 0.52; 95% confidence interval 0.29 to 0.94; p-value = 0.03) and a relative risk reduction of 48% ⁵ .

The most widely accepted theory on how CP acts in SARS-CoV-2 infection is by neutralizing antibodies inhibiting viral entry and amplification, mediating viral clearance, activating complement, enhancing the dependent cellular phagocytosis, and cytotoxicity, and providing anti-inflammatory cytokines ^{6, 7} .

However, CP may also have a long-term negative effect by down-regulating the inflammatory response (a decrease in activated, effector, and memory CD4 ⁺ T cells, a decrease in activated and effector CD8 ⁺ T cells, and a decrease of naïve B cells) ⁸ , suppressing antibody formation ⁹ and promoting autoantibodies against interferons ¹⁰ .

COVID-19 CP proved to be a safe intervention with <1% severe adverse events immediately after its administration ² . Nevertheless, the long-term clinical effects of COVID-19 CP are to date understudied.

Our objective was to establish the long-term safety profile of COVID-19 CP and determine if its administration increases the risk for further respiratory infections in older adults.

Study population. The study by Libster et. al. included 160 mildly symptomatic participants infected with SARS-CoV-2 who were 75 years of age or older, or between 65 and 74 years of age with at least one coexisting comorbidity (hypertension, diabetes, obesity, chronic renal failure, cardiovascular disease, and COPD) ⁵ . Participants were randomized 1:1 to receive 250 ml of convalescent plasma (with an IgG titer > 1:1000 against SARS-CoV-2 spike protein) or 250 ml of placebo (0.9% normal saline) in less than 72 hours since the onset of symptoms. Next, they were strictly followed for 15 days to evaluate the development of severe respiratory disease ⁵ .

All patients included in the intention to treat (ITT) analysis of the original RCT study ⁵ were invited to participate in a prospective cohort to assess for clinical differences over time among the CP and the placebo groups.

From the initial RCT that included a total of 160 patients in the ITT analysis (CP=80 and Placebo=80) and 154 in the mITT (CP=76 and Placebo=78), 153 were eligible to participate in the study (6 died during the original study and 1 withdrew consent). 142 patients were included in the follow-up study. 10 patients were lost to follow-up and 1 patient did not want to participate in the follow-up study, resulting in a total retention rate of 92.8% (CP=92.3% vs Placebo=93.3%) ( Figure 1).

The mean age of included participants was 77.2 years (SD 8.6), and their median duration of follow-up was 10.4 months (IQR 1.63), with no differences among groups, with 10.3 months (IQR 1.68) and 10.42 months (IQR 1.6) for the CP and placebo groups respectively (t-value (df 140) =-0.35, p-value=0.724). No treatment switching was evidenced during the follow-up time. 89% of the participants (n=127) received a COVID-19 vaccine during the study with a median time to the first dose of 8.8 months (IQR 2.2).

14% of the participants (n=20) had a clinically confirmed ARI during the study. No differences were observed between groups (CP=11/72 and Placebo=9/70, x ² =0.17, p-value=0.678). The median time to first ARI was 8.63 months (IQR 7.13) for the CP group and 9.2 months (IQR 7.53) for the placebo. No statistically significant differences were observed in the probability of ARI-free survival between groups (log-rank test p-value=0.63) ( Figure 2).

CP and placebo patients did not present any adverse event related or probably related to the investigational products during this follow-up study. No differences emerged when comparing groups regarding total SARS-CoV-2 reinfections (CP=1/72 vs Placebo=1/70, x ² =0.0004, p-value=0.984), all-cause mortality (CP=5/72 vs Placebo=2/70, x ² =1.27, p-value=0.261), and in the number of patients with persistence of COVID-19 symptoms after the initial infection (CP=34/72 vs Placebo=30/70, x ² =0.27, p-value=0.601).

There were no statistically significant differences in the number of participants with ARI when comparing within the mITT subgroup (CP=10/69 and Placebo=9/68, x ² =0.045, p-value=0.831) or when comparing those who received SARS-CoV-2 S IgG titer in donor plasma ≥1:3200 vs. placebo (CP=3/34 and Placebo=9/70, x ² =0.36, p-value=0.546). All secondary endpoints remained stable with no difference by treatment in the subgroup analyses (data not shown).

In this post-trial follow-up study of an RCT of COVID-19 convalescent plasma in older adults, CP did not increase the risk for acute respiratory infections in the long-term follow-up. Furthermore, no differences were observed between groups (CP vs placebo) when assessing for time to first acute respiratory infection, adverse events, SARS-CoV-2 reinfections, all-cause mortality, and persistence of COVID-19 symptoms. In addition, all endpoints remained stable showing no difference in the subgroup analyses.

To our knowledge, this is the first post-trial follow-up after an RCT of COVID-19 CP assessing for long-term consequences of its administration. COVID-19 convalescent plasma remains a safe intervention with no clinical consequences in the long term.

A recent randomized clinical trial with control plasma by Sullivan et al. supports the hypothesis of our original study that COVID-19 CP should be administered early in the course of the disease and to those presenting mild symptoms ¹¹ . In this study, COVID-19 CP presented a relative risk reduction of 54% in COVID-19 related hospitalization within 28 days after transfusion, which increased to 79.9% in those with ≤ 5 days of symptoms. However, no differences were found between groups when comparing patients already vaccinated ¹¹ .

Our study adds evidence to the long-term safety of COVID-19 CP. This intervention might have now a lesser role as a strategy against SARS-CoV-2, however, our study supports an early and coordinated evaluation of convalescent plasma use in future pandemics.