DISCUSSION
Our analysis of IVIG lots revealed high nAb titers to HCoV-229E (Figure 1B), which confirmed the presence of functionally intact nAbs in these lots. It is interesting to note that in IVIG lots produced from recovered plasma significantly higher titers to HCoV-229E were found compared to IVIG lots produced from source plasma, independent of plasma origin. Recovered plasma is usually obtained from older donors [11]. A trend towards increasing probability of HCoV-229E infections with age has been detected in the Scottish [3] and US [4] population. Furthermore, higher HCoV-229E–specific nAb titers were found in older study participants (60–85 years) compared to younger ones (21–40 years) [12]. Thus, a higher infection rate with HCoV-229E in older people and consequently the generation of neutralizing HCoV-229E–specific antibodies in the older plasma donors would explain the higher HCoV-229E titers found in IVIG lots produced from recovered plasma.
Low levels of cross-neutralizing Abs have earlier been demonstrated between specific pairs of coronaviruses, specifically between SARS-CoV-2 sera and SARS-CoV [6] and SARS-CoV sera and MERS [13].
In clear contrast, testing the same lots of IVIG that were shown to contain high HCoV-229E nAb titers with a highly specific SARS-CoV-2 µNT did not detect SARS-CoV-2–specific nAbs. These results are entirely consistent with the absence of SARS-CoV-2 antibodies in the plasma used for production of these IVIG lots, as this plasma was donated well before the start of the SARS-CoV-2 pandemic.
The current study, as well as an earlier study that tested 21 IVIG lots (9 Gamunex C, 10 Gammagard Liquid, 2 other) with a SARS-CoV-2-specific enzyme-linked immunosorbent assay (ELISA; receptor-binding domain or spike protein) that was shown to correlate well with a neutralization test [14] revealed the absence of cross-reactive antibodies against SARS-CoV-2 in IVIG lots produced from prepandemic plasma. Currently available IVIGs can therefore not be expected to afford protection from SARS-CoV-2 infection. Nevertheless, several clinical trials currently investigate IVIG at high dosage in the treatment of COVID-19 patients (clinicaltrials.gov), with the expected benefit attributable to the anti-inflammatory and immunomodulatory capacity of IVIG, rather than an antiviral effect.
With increasing numbers of human infections, including in the plasma donor community, it is interesting to follow the development of antibodies against SARS-CoV-2 in plasma donations and, after the several months production cycle time between plasma donation and IVIG lot release, also in IVIG lots. A longitudinal study on this topic is currently in progress. In this context it is noteworthy that the mean nAb titers induced by WNV [1] and SARS-CoV-2 [9] infection are of similar magnitude. After the emergence of WNV in the United States, nAb titers became detectable in IVIGs after approximately 0.5% of the population had contracted and recovered from the infection. In Austria, testing of plasma pool samples indicated that up to 1.17% of plasma donors were positive for SARS-CoV-2 nAbs. Based on the current number of reported SARS-CoV-2 infections in the United States (approximately 4.3 million per 30 July 2020; www.cdc.gov), and an estimated rate of >40% asymptomatic infections [15], more than 7.2 million people in the United States could have been infected already, that is 2.2% of the approximately 330 million population. Based on these facts, the detection of SARS-CoV-2 nAbs in IVIG lots produced from US plasma, the major source for fractionation, is expected within the next few months.
Another, more immediately available possibility for the treatment of COVID-19 is production of a hyper-IVIG from the plasma of COVID-19 convalescent donors (CoVIg-19), and developmental work is currently under way through a large alliance of plasma stakeholders (https://www.covig-19plasmaalliance.org).