In line with a previous report for Wuhan SARS-CoV-2 wild type virus , IG fractionated from plasma collected prior to the COVID-19 pandemic did also not neutralize the Omicron SARS-CoV-2 variant (Fig. 1). COVID-19 HIG preparations, fractionated from COVID-19 convalescent donor plasma collected at the beginning of the pandemic and therefore representative of the antibody response to infection only, provided for some Wuhan as well as Omicron neutralization, with the latter however considerably lower than against the Wuhan SARS-CoV-2 wild type, in line with previous reports of 16-fold and up to 32-fold lower neutralization of the Omicron vs. Wuhan strain by post COVID-19 sera, tested with a pseudovirus system [10, 11].
The difference in Wuhan versus Omicron neutralization potency was somewhat less pronounced for pandemic IG preparations (Fig. 1), manufactured from plasma collected from a mixed convalescent, COVID-19 vaccinated and partially even re-exposed donor population. The highly potent and heterogeneous SARS-CoV-2 antibody specificities contained in these commercial IG lots apparently provide for better Omicron neutralization, reflective of the greater antibody response to COVID-19 vaccination rather than SARS-CoV-2 infection only [1, 12] and broader Omicron neutralization following repeat vaccination and infection exposures [11, 13]. Still, the observed differences in SARS-CoV-2 variant cross-neutralization by the IG preparations support the proposal to consider the Omicron SARS-CoV-2 variant a distinct serotype .
A dramatic upward change in anti-SARS-CoV-2 potency was previously reported for US plasma-derived IG lots released in May 2021 , a trend that continued until the end of 2021 and seems to have plateaued since then (Fig. 2A), irrespective whether IG preparations for intravenous or subcutaneous application were analyzed (Fig. 2B). Analysis of EU plasma-derived IG lots indicated that SARS-CoV-2 neutralization titers against the Wuhan virus strain were lower in May 2021, reflective of the lower COVID 19 incidence as well as slower uptake of vaccination in Europe as compared to the US . By the end of 2021, Wuhan SARS-CoV-2 wild type neutralizing titers in EU-plasma derived IG lots had reached equivalently high levels as in US-plasma derived IG lots.
First Omicron cases were reported in November 2021 from the US and EU  and the variant then rapidly became dominant in both geographies. With a typical period of approximately 6 months between plasma collection and IG lot release , Omicron-induced antibodies are not yet likely present in the IG preparations investigated here, although an increase in (cross-)neutralization titer also against the new variant is evident in US- and EU-plasma derived IG lots released in March and April 2022, which is expected to further increase significantly in the IG lots released in the upcoming months.
This outlook is of relevance for people with immunodeficiencies or immunosuppression, who depend on the antibody specificities contained in their IG treatment for protection from COVID-19. In the US, the COVID-NET has analyzed factors associated with severe outcomes in over 22,000 adults hospitalized with COVID-19. Of these, 12.2% were immunocompromised, although they only constitute an estimated 2.7% of the entire US population .
More specifically to the Omicron virus variant, plasma samples from patients with X-linked agammaglobulinemia, who receive regular IG as prophylaxis, were found to contain relatively low plasma concentrations of SARS-CoV-2 antibodies, with no potential to neutralize the Omicron variant in vitro, and three out of four patients had symptomatic COVID-19 during the Omicron wave . The most current IG lot used in this study was produced in August 2021, i.e., at a time when SARS-CoV-2 neutralization titers of US plasma-derived lots were 4–5 times lower than reported here for current IG lots, and lower yet for EU plasma-derived lots (Fig. 2A). Whether these more potent antibody levels, now also against the Omicron virus variant, driven by additional COVID-19 cases and even more so effective vaccination campaigns, will be able to afford clinically meaningful levels of protection remains to be determined.