SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Show Markedly Reduced Cross-reactivities Against Omicron Variants

Abstract

Purpose Patients with antibody deficiencies often receive maintenance treatment with donor plasma-derived immunoglobulin (Ig) preparations to decrease the incidence and severity of infections. We have previously shown that IgG antibodies to the original SARS-CoV-2 strain were not consistently present in off-the-shelf Ig batches produced up to approximately 18 months after the first identified case of COVID-19 in the USA and that Ig batches with anti-SARS-CoV-2 IgG primarily contained vaccine-induced spike specific antibodies. This study aimed to investigate the degree of cross-reactivity between vaccine-induced anti-SARS-CoV-2 antibodies against Wuhan strain and subsequent viral variants. Methods Samples were collected from 74 Ig batches supplied by three different commercial manufacturers. All batches were used at the Immunodeficiency Unit at the Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until September 2022. Antibody quantity and potential to neutralize virus entry into host cells were assessed against the original SARS-CoV-2 Wuhan strain and the following nine variants: Alpha, Beta, Delta, IHU, and the Omicron BA.1, BA.1.1, BA.1 with spike mutation L452R, BA.2, and BA.3. Results Ig batches produced approximately 18 months after the SARS-CoV-2 outbreak (from around July 2021) and later consistently contained high quantities of antibodies that bind the Wuhan strain. The Ig batches had overall low reactivity to the SARS-CoV-2 nucleocapsid, which implies that plasma donor spike IgG essentially is the result of vaccination. We assessed the degree of cross-reactivity towards each virus variant by plotting the variant/Wuhan strain ratio, which was consistent regardless of production date, suggesting cross-reactivity with vaccine-induced antibodies rather than virus exposure in the plasma donor population. Viral variants that emerged later during the pandemic systematically had a lower reactivity ratio, except for the Delta and IHU variants. The Ig batches displayed markedly low neutralizing potential towards the Beta variant and all tested Omicron variants. Conclusion Commercial Ig batches currently contain large quantities of SARS-CoV-2 vaccine-induced antibodies. Cross-reactivity with variant strains is evident but varies, with markedly low neutralizing potential observed against Omicron variants.

Immunoglobulin replacement products confer in vivo protection against SARS-CoV-2 XBB.1.5 Omicron variant despite poor neutralizing activity

“…No significant difference was observed in neutralizing activity of IG products against the WA1/2020 D614G and Delta strains over many months ( Figure 2C ). This finding was consistent with results from 2 studies that examined neutralizing activity of the Delta variant by commercial IG products ( 8 , 13 ) and 1 that followed individuals immunized with mRNA vaccines, with or without history of COVID-19 infection ( 18 ). Neutralizing activity against Omicron BA.1 strain was not observed in infused products until April 2022, 4 months after Omicron began circulating in the United States ( Figure 2C ).…”

“…Another study showed that IG products that efficiently blocked WA1/2020 D614G spike binding to the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2) had poor inhibitory activity against binding of Omicron BA.1 spike to ACE2 ( 8 ). Poor neutralizing activity of IG products against Omicron strains BA.1 and BA.1.1 was also observed in another study ( 13 ). At present, there are no data to our knowledge on the neutralizing activity of IVIG and SCIG against the more recently emerged XBB.1.5 strain or in vivo protective activity of currently available IG replacement products against circulating SARS-CoV-2 variants.…”

Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program

“…Although this was a significant increase, the GMT is still considered low compared to the trajectories of the other cohorts. Fourteen of these participants received IGRT, which may also explain the increase due to increasing levels of anti-S antibodies in those preparations at the time ( 24 ). Previously, we found that the presence of a noninfectious complication with or without the use of immunosuppressive medication was negatively associated with response after two mRNA-1273 vaccinations.…”

“…Besides, the usefulness of giving virus-specific boosters for the aim of boosting (cross-reactive) T-cell responses is not clear yet. Rising levels of (neutralizing) antibodies in IGRT preparations offer perspective in these patients, although these preparations may have limited effect against newer variants because of the delay between plasma donations and their clinical use in IGRT preparations ( 24 ). Lastly, we argue that continued research into other therapies, such as antivirals, is needed to protect IEI patients from severe illness after contracting COVID-19 as well as for other endemic viruses and future virus outbreaks.…”

“…Nucleocapsid (N)-specific IgG antibodies were analyzed to identify participants who contracted COVID-19 before or during the study. We selected a cutoff value with 100% specificity, measured in pre-pandemic sera from healthy donors, to minimize the possibility of false-positive results due to administration of (low levels of) N-specific antibodies in IGRT ( 23 , 24 ). Therefore, an infection with SARS-CoV-2 was defined as a history of a positive PCR test, positive antigen test, and/or an N-specific IgG titer above 42.2 BAU/ml.…”