key: cord-1013751-yxa7gw01
authors: Paik, Julie J.; Sparks, Jeffrey A.; Kim, Alfred H.J.
title: Immunogenicity, breakthrough infection, and underlying disease flare after SARS-CoV-2 vaccination among individuals with systemic autoimmune rheumatic diseases
date: 2022-05-02
journal: Curr Opin Pharmacol
DOI: 10.1016/j.coph.2022.102243
sha: 0d586dc29daa938b1f558f20125b140ad9ced674
doc_id: 1013751
cord_uid: yxa7gw01

Many patients with systemic autoimmune rheumatic diseases (SARDs) require immunosuppression to reduce disease activity, but this also has important possible detrimental impacts on immune responses following vaccination. The phase III clinical trials for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines did not include those who are immunosuppressed. Fortunately, we now have a clearer idea of how immune responses following SARS-CoV-2 vaccination has for the immunosuppressed, with much of the data being within a year of its introduction. Here, we summarize what is known in this rapidly evolving field about the impact immunosuppression has on humoral immunogenicity including waning immunity and additional doses, breakthrough infection rates and severity, disease flare rates, along with additional considerations and remaining unanswered questions.

Immunosuppressed individuals with systemic autoimmune rheumatic diseases (SARDs) may be vulnerable to both Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- infection and severe Coronavirus Disease 2019 (COVID-19) outcomes [1] [2] [3] [4] . Therefore, SARS-CoV-2 vaccination may be especially crucial for individuals with SARDs. However, the SARS-CoV-2 vaccine clinical trials did not include SARDs or other immunosuppressive conditions. Immunosuppressive medications and underlying altered immunity may impact vaccine immunogenicity and result in lower effectiveness, resulting in breakthrough infection after vaccination. Specific immunosuppressive medications may particularly impact SARS-CoV-2 vaccine response and also affect the immune response to SARS-CoV-2 infection 5 . Temporary discontinuation around SARS-CoV-2 vaccine doses has been proposed to optimize immune response 6 . However, immunosuppressive medication disruption and immune activation after vaccination could also lead to underlying SARD flares and increased disease activity. Also, it is possible that the immune response may wane more quickly in immunosuppressed individuals than the general population, necessitating the need for additional vaccine doses. Finally, immunosuppressed patients may have prolonged viral shedding that may introduce new variants 7, 8 . Thus, there are a myriad of considerations patients and providers with SARDs must balance related to SARS-CoV-2 vaccination.

In this narrative review, we will provide an overview of the current evidence related to humoral immunogenicity from SARS-CoV-2 vaccination, focusing on specific immunosuppressive drugs, waning immunity, medication discontinuation around vaccination, and additional doses. We will also discuss the studies investigating clinical cases of breakthrough infection after vaccination. Finally, we will detail studies investigating disease flare or increased disease activity after SARS-CoV-2 vaccination.

Humoral response in immunosuppressed patients with rheumatic and musculoskeletal diseases have been reported to be diminished [9] [10] [11] [12] . It is now well appreciated that depending on the type of immunosuppressive therapy, such as B-cell depleting agents and mycophenolate mofetil, the antibody response can be dampened significantly. It is not surprising then that rheumatic patients treated with such agents would be more vulnerable to severe COVID-19 infection despite vaccination. This section will review the body of evidence that supports how different immunosuppressive therapies can blunt the humoral response (see Figure 1) .

B cell-depleting agents, such as rituximab, have been reported to be the most significant offender in reducing humoral response after SARS-CoV-2 vaccination [12] [13] [14] [15] [16] . In fact, some studies have demonstrated that patients who receive rituximab do not mount any antibody response which in particular can be concerning for those on maintenance therapy. Duration since rituximab exposure may be an important contributor to improved humoral response 17 . In a retrospective study of 56 patients treated with rituximab, the longer the period between the patient's last exposure of rituximab and SARS-CoV-2 vaccination was associated with a positive serologic response, with those who had exposure >12 months had the best response 18 .

Additionally, B-cell reconstitution has been reported to be a reliable marker of seroresponse in those with vasculitis or rheumatoid arthritis 14, 17, 18 .

Mycophenolate mofetil and mycophenolic acid have been reported in multiple studies to blunt the humoral response 12, 19 . In the rheumatic arm of the national vaccine response study at Johns Hopkins, patients taking mycophenolate reported rates of seroconversion as low as 27% after the first dose of the SARS-CoV-2 mRNA vaccine, with improvement to 73% after the second dose 9, 12 . Even more reduced response has been reported in patients on anti-metabolite J o u r n a l P r e -p r o o f regimens containing MMF in single organ transplant recipients 11, 19 . Interestingly, azathioprine has not been reported to have a significant impact on the humoral response 12 .

Methotrexate has been reported to have lower rates of seroconversion, but reports have not been consistent 9, 10, 16, 19 . For example, in the Johns Hopkins cohort, there was no significant impact of methotrexate on humoral response. However, in other cohort studies that included a US based cohort at New York University Langone with a European validation cohort, humoral immune response was diminished. Only 62.2% of patients on background methotrexate demonstrated an adequate response after two-dose vaccination 20 .

The dose of glucocorticoids and its direct effects on humoral response after SARS-CoV-2 vaccination still needs further study. However, since most people with SARDs are on combination therapy with other immunosuppressants, it may be difficult to isolate the sole effects of steroids alone. Nonetheless, a well characterized US cohort study, the COVARiPAD study, demonstrated that antibody titers were lower in patients who receive low dose prednisone (<7.5mg/daily) 10 .

In one of the largest observational studies of 686 patients with rheumatic diseases, seroconversion was lower for those on immunosuppression, such as abatacept (71% seroconverted), JAK inhibitors (90% seroconverted), while other immunosuppresants (leflunomide, hydroxychloroquine, TNF inhibitors, IL-6 inhibitors, and IL-17 inhibitors) did not significantly impact seroconversion 21 

While antibody responses are detectable for a minimum of 6 months following the initial series of SARS-CoV-2 mRNA vaccination in immunocompetent individuals 22, 23 , titers do tend to wane during this period potentially leading to loss of protective responses. Due to attenuated humoral responses associated with immunosuppression, the impact immunosuppression has on antibody decay kinetics is critical to inform providers about the need for additional boosting or administration of pre-exposure prophylaxis.

Data is starting to emerge suggesting that most individuals with SARDs on immunosuppression likely maintain antibody titers that are protective. Data from the Johns Hopkins cohort revealed that while anti-RBD titers reduced by 2.8-fold between the 1-month to 6-month post-vaccination period, 96% of the study participants remained seropositive (96%) and 80% continued to maintain predicted protective neutralizing antibody titers 24, 25 . Those on monotherapy had the high rates of high antibody titers compared to participants on combination therapy, and similar to antibody responses immediately post-vaccination those on therapies that B cell modulating therapies and T cell co-stimulation blockade were seronegative at the 6-month timepoint 24 . These early findings should be encouraging for immunosuppressed patients with SARDs, as initial antibody responses appear to be predictive of durable responses.

An additional 3rd SARS-CoV-2 vaccine dose in those who had a poor antibody response have found that up to 80% seroconvert in a case series of 18 patients 26 . Similarly, a fourth dose has also been reported to improve humoral response in a case report of a patient with rheumatoid arthritis even without pausing immunosuppression 27 . Interestingly, another case series of 18 patients from the Johns Hopkins cohort also demonstrated that a 4th additional dose augmented humoral response 28 . However, there was a subset of patients who did not hold immunosuppression who remained persistently negative.

Beyond additional vaccine doses, peri-vaccination hold of immunosuppressants can be a complementary strategy to improve humoral response in rheumatic patients on immunosuppression. Peri-vaccination hold of mycophenolate mofetil has been reported to augment humoral response in rheumatic patients 29 . In a case series of 24 patients who withheld mycophenolate, 22/24 (92%) had detectable antibodies compared with 112/171 (65%) who continued therapy. There were two participants who reported flares of their underlying disease requiring treatment in the peri-vaccination period, therefore careful assessment of disease activity should be done when optimizing vaccination strategies. 

In one of the largest physician-reported registries of inflammatory/autoimmune rheumatic musculoskeletal diseases (n=5121 participants from 30 countries), it was found that flares were 45 . This suggests that immunosuppressive medication changes around vaccination, rather than vaccine-specific effects, could explain at least some RMD flares after vaccination.

Overall, risk of severe flare after COVID vaccination was relatively uncommon in multiple studies and may be similar to the baseline rate of SARDs. These findings emphasize the safety of SARS-CoV-2 vaccines for immunosuppressed patients with SARDs.

In the immunocompetent population, germinal center (GC) responses in draining lymph nodes last for a minimum of 6 months 46 which are critical for optimizing antibody diversity, affinity, and function. The duration of GC responses likely has major implications for the immunosuppressed: if immunosuppression is held peri-vaccination, restarting these medications likely are occurring early in the GC response. Blunting GC responses will theoretically attenuate cross-variant neutralization responses, as observed in the setting of MMF or TNFi. GCs are absent in patients who underwent kidney transplantation, partially due to the use of MMF 47 

Within a year of the introduction of SARS-CoV-2 vaccines, we impressively have a solid idea of how various classes of immunosuppressive influence antibody titers. But these data have open additional questions regarding the relationship between immunogenicity, protection, and the complete impact of immunosuppression has on both. For example, all studies have found large variation in antibody titers among study participants for any given immunosuppressive class. Whether this is due to concomitant medication use, disease state or activity, sleep quality (as has been observed with hepatitis A vaccination 57 ), or host genetics will require additional efforts to deconvolute.

Furthermore, these responses assessed immediately after SARS-CoV-2 vaccination do not fully represent the mature humoral response. As discussed above, germinal center responses linger for months after vaccination in the immunocompetent which serves to improve antibody quality by diversifying antibody repertoire. We only have a limited idea of the impact of immunosuppression on antibody quality, which is limited to TNFi. This has implications on whether to hold medications, as they will be restarted when germinal center responses are clearly ongoing. The NIH/NIAID-sponsored ACV01 clinical trial, which seeks to examine the impact of additional doses of SARS-CoV-2 vaccine and holding either methotrexate or mycophenolate on antibody and cellular responses 58 .

Finally, questions remain about the robustness and importance of T cell responses particularly for non-B cell depletion therapies. Also, the generation of mucosal immunity vis-a-vis S-specific IgA remains unclear, with little data published thus far 59 . As these and other questions are answered over the following months and years, this will provide the most comprehensive collective dataset that will certainly inform about how to improve the outcomes with other vaccines these patients require. 

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One of the first prospective studies demonstrating the importance of how different immunosuppressants affect immunogenicity of SARS-CoV-2 vaccines

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One of the earliest observations demonstrating the negative impact of immunosuppression, especially mycophenolate and rituximab, on antibody reponse after SARS-CoV-2 vaccination

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One of the largest observational studies highlighting that seroconversion was lower in those taking abatacept while others did not significant impact seroconversion (such as leflunomide, IL-6 and IL-17 inhibitors)

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Similar to ref 46, paired blood and draining lymph node specimens from kidney transplant recipients were examined to identify the absence of GCs and neutralizing antibody responses

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One of the first reports to examine cross-variant neutralization responses using infection SARS-CoV-2 virus, identifying the lack of response to Beta and Delta variants in TNFi users

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