As you know I have had to backpedal with my SARS-CoV-2/COVID-19 advice in relation to anti-CD20 therapies. I have now had to reinterpret data on the role of immunoglobulins in protecting people from developing COVID-19 and severe COVID-19.
I have been using the two Italian cases of X-linked agammaglobulinaemia who got COVID-19 and make a recovery as an argument that you don’t need B-cells and immunoglobulins to recover from SARS-CoV-2 infection. I now think I am wrong. Both these patients were being managed with immunoglobulin replacement therapy or IVIG (intravenous immunoglobulin therapy). IVIG is essentially a mix of immunoglobulins from blood donors from the general population. The assumption I made was that as SARS-CoV-2 was a new virus there would be no antibodies in the general population that would neutralize the SARS-CoV-2. However, the study below shows that pooled immunoglobulin therapies are able to neutralise SARS-CoV-2 (see Díez et al. below). Therefore I can’t assume, based on these two cases, that you don’t need immunoglobulins to make a recovery from COVID-19. This observation of neutralizing anti-SARS-CoV-2 activity in IVIG is also compatible with the emerging data that rituximab and by implication other anti-CD20 therapies now appear to increase your chances of getting COVID-19 and severe COVID-19.
I suspect anti-CD20 therapies increase your chances of getting COVID-19 by reducing your chances of having an asymptomatic SARS-CoV2 infection. The immune responses to other human coronaviruses, the ones that cause the common cold, cross-react and help neutralise SARS-CoV-2, which explains why some people get asymptomatic or mild SARS-CoV-2 infections (see Shen et al. below). However, if you are B-cell depleted when getting the common cold, due to coronavirus, your immune system isn’t able to make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting COVID-19.
In support of this the case study published last week of a person with MS on ocrelizumab who failed to seroconvert to having anti-SARS-CoV-2 antibodies despite having confirmed SARS-CoV-2 COVID-19 (see Conte. case report below). This particular patient had mild hypogammaglobulinaemia as a result of ocrelizumab treatment. The failure to seroconvert could be an assay problem, i.e. low sensitivity, or is more likely to be due to the blunted B-cell response from being treated with ocrelizumab. Clearly this case report is going to be very important in shaping our thinking in terms of doing further anti-SARS-CoV-2 seroprevalence studies in people with MS and preparing our patients for a potential SARS-CoV-2 vaccine. The latter gets more pressing as most countries have now abandoned herd immunity as a strategy to deal with COVID-19.
Background: There is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy.
Methods: The neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT50) in the PFU assay and the half maximal inhibitory concentration (IC50) in the cytopathic/cytotoxic method (calculated as the minus log10 dilution which reduced the viral titer by 50%).
Results: All IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV.
Conclusion: In cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management.
Conte. Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab with hypogammaglobulinemia. MSARDS June 20, 2020.
Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.