This study reports the cumulative incidence of the COVID-19 Omicron variant in fully vaccinated patients with HD in comparison with HCW. We also showed the longitudinal changes in the antibody response and Ct values.
To the best of our knowledge, this is the largest study on the patients with HD investigating the prevalence of COVID-19 since the Omicron waves occurred and the booster vaccination was implemented. A pivotal trial that demonstrated the clinical efficacy of the mRNA vaccine against Omicron included a large number of immunocompetent and relatively younger individuals, with only 0.8% of the population being immunosuppressed.6 Moreover, many studies extensively focused on the impaired antibody response after vaccination in HD patients,14,19 which may not correspond to the real-world susceptibility to the Omicron variant. Interestingly, the present study showed that patients with HD were less likely to develop a breakthrough infection than HCW despite potentially having more vulnerable characteristics, including older age, lower antibody titers, and disease- and/or treatment-induced immunosuppression. This disparate COVID-19 prevalence was similar to that in a previous report that was predominantly included patients with cancer.20 In addition, the recent exposure to B-cell depletion therapy, which is a leading contributor to diminished humoral responses, was no longer a significant factor for the increased risk of breakthrough infection in the D3-cohort. Altogether, our results may suggest that behavioral factors, such as social activity and social distancing measures may be more important than immunological profiles in preventing Omicron infections, at least after booster vaccination.
The Omicron variant has been found to have multiple mutations in its spike protein, which is responsible for immune evasion to neutralize vaccine-induced antibodies.21 Vaccine effectiveness is thought to be correlated with antibody titers, although higher antibody levels are anticipated to be required to neutralize Omicron, it is still unclear whether they confer an actual protection against infection. Stærke et al. showed the limited impact of quantitative levels of anti-spike IgG on the risk of Omicron breakthrough infection in contrast to the Delta variant in the general populations.22 In line with their report, a dose-dependent association between anti-S levels and the risk of infection was not observed in the D3-cohort. In contrast, it has been observed that no protective effect against Omicron BA.1 is seen with less than about 6000 binding antibody units/mL, and that 20 000 units are required for a protective effect of more than approximately 90%.23 Given the reduced levels of post-D3 anti-S (less than half of HCW) which further decreased by over 10% per month, the protection against Omicron driven by anti-S levels, even if it exists, is likely to have a lesser degree and shorter duration in patients with HD. Additionally, given the immune escape properties of Omicron, protection may require extremely high antibody titers,23 or antibodies that are more specific to Omicron than conventional antibodies.24
In the present HD cohort, which included 17.3% of seronegative patients after full vaccination, only three patients (4.0%) died of pneumonia associated with COVID-19 infection. In addition, only 9 (12.0%) patients with oxygen demand required hospitalization. The remaining patients were treated at outpatient or did not required treatment owing to their mild symptoms with early recovery. The mild symptoms of infection and the low mortality rate, even in patients with low antibody titers, suggest that the Omicron variant itself causes less frequent and less severe pneumonia than previous variants. These observations were consistent with the results of ex-vivo cell cultures of human lungs and analyses in mice, which showed that the Omicron mutant replicated less efficiently in the lungs than other mutants and exhibited mild pathological lung inflammation.25,26 These low hospital admissions and mortality rates are comparable with larger immunocompetent cohort with Omicron variant infections, and are reduced from those seen with the Delta variant based on studies in South Africa and Canada.10,27
Prolonged viral shedding of SARS-CoV-2 including Omicron variant was previously described in several case reports and series with severe immunocompromised patients with HD.16,28−29 In our cohort, there was no difference in the frequency of infection with Omicron variants between patients treated with CD20 antibodies plus bendamustine and those treated with drugs other than bendamustine within one year. However, in patients with available longitudinal PCR data, delayed viral shedding was observed in five patients with Omicron infection who received CD20 antibody therapy plus bendamustine, whereas patients who did not receive the bendamustine did not have delayed viral shedding.
The factors leading to delayed viral shedding include a varying degree of T-lymphocyte reduction in persistently infected patients, possibly associated with the use of bendamustine, while CD19 counts did not differ between the two groups. T-cell immunity has been reported to be important for the control of and recovery from COVID-19 infection,30 especially in patients with impaired humoral immunity.31 In addition to persistent infection, suppression of T-cell immunity was related to increased mortality.31 In our cohort, all three patients who died of COVID-19 related pneumonia did not receive a booster dose of vaccination; booster vaccination does not only dramatically increases neutralizing antibody titer,32 but may also enhance T-cell reactivity to the Omicron variant.33 In addition, the clinical report that booster dose of vaccination reduced hospitalization and death by Omicron variant compared with two doses of vaccination34 is consistent with our observations.
The strength of this study is the largest cohort with detailed clinical information in combination with serological data of patients, including viral kinetic assessment. However, there are several limitations in related to the study design and methodological issues. First, we could not directly measure the neutralizing antibody against Omicron. However, the anti-S assay is more widely accessible, cost- and time-effective than the neutralization assay, and has also been shown to correlate with neutralization in Omicron.32 Garcia-Beltran et al. showed that the optimal cut-off of anti-S for predicting minimum neutralization against Omicron was up to 10300 U/mL, which supports our findings of the limited impact of quantitative anti-S levels on protection against infection.32 The low incidence of breakthrough infections makes it difficult to adjust potential confounding factors. Furthermore, this study was conducted during a limited time window when Omicron became predominant with a wide distributions of existing mRNA vaccines. Therefore, our data could not be directly compared with the pre-Omicron era data and extrapolated to future variants. Prophylaxis against Omicron variants has been developed through vaccination with bivalent vaccines35,36 and monoclonal antibodies such as tixagevimab and chilgavimab.37,38 However, given the antibody response to vaccines and its attenuation in HD patients, there is a possibility that antibody production to these bivalent vaccines may not be sufficient to prevent breakthrough infections, rather passive immunization with the latter may be more effective, although this should be evaluated in the context of clinical practice.
Finally, we only analyzed T-cell subset counts between patients with non-persistent and persistent infection. Our study lacks the functional analysis of T-cell immunity (i.e., T-cells response to specific antigens or T-cell exhaustion); however, T-cell subset count is a commonly available method in real world clinical settings and easily estimate the impaired T-cell immunity. Bange et al. also reported that recovery from COVID-19 was highly dependent on the CD8 T-cell count in patients with hematologic malignancies in the setting of defective humoral immunity.31