The Impact of Immune-Modifying Treatments for Skin Diseases on the Immune Response to COVID-19 Vaccines: a Narrative Review

Purpose of Review SARS-CoV-2 has had a devastating global effect, with vaccinations being paramount in the public health strategy against COVID-19. Vaccinations have uncoupled infection from adverse COVID-19 outcomes worldwide. While immune-modifying therapies are effective for the management of skin diseases such as psoriasis and atopic dermatitis, these medications also impair protective immune responses. There has been longstanding uncertainty and concern over the impact of immune-modifying therapies on the effectiveness of vaccines; for example, it is well recognised that methotrexate impairs humoral responses to both influenza and pneumococcal vaccines. This narrative review aims to discuss the evidence to date on the impact of immune-modifying therapies on the immune response to COVID-19 vaccines, with a focus on the first two vaccine doses. Recent Findings Individuals receiving immune-modifying therapy are more likely to have attenuated humoral responses to a single dose of COVID-19 vaccine compared to healthy controls; however, this may be improved by a complete course of vaccination. B cell targeted biologics such as rituximab markedly impair the humoral response to both the first and second COVID-19 vaccination. There remains a paucity of data on cellular immune responses, with the few available studies indicating lower responses to two vaccine doses in individuals receiving immune-modifying therapies compared to healthy controls, which may impact the durability of immune responses. Summary Inadequate humoral immune responses to a single dose of vaccine in the context of immune-modifying therapy are improved by a complete course of vaccination. Individuals receiving immune-modifying treatments should be encouraged to take up a complete vaccine course to mitigate their risk against COVID-19. Research in large patient populations on the longevity/kinetics of the complex humoral and cellular response to subsequent vaccine doses, including against newer variants of concern, is warranted, in addition to data on immune correlates of vaccine clinical effectiveness.


Introduction
Immune-modifying therapies have improved clinical and quality of life outcomes of individuals with immune-mediated skin diseases such as psoriasis, atopic dermatitis and immunobullous disease. However, these medications can also impair protective immune responses [1,2]. COVID-19 vaccination programmes have seen great success, with reassuring safety data and two doses of COVID-19 vaccines reported to be 89-97% effective against the development of symptomatic infection in the general population (data pertain to older SARS-CoV-2 variants such as Alpha, Beta, Delta, Gamma) [3]. Given that infectionacquired immunity is limited in duration and susceptible to variants, vaccines are important for mitigating against severe COVID-19 outcomes [4,5]. Due to concerns over the effectiveness of vaccines in individuals who are receiving immunemodifying therapies, the impact of these medications on the immune response to COVID-19 vaccinations has been an area of intensive investigation [6].
Immune-modifying therapy can be divided into two broad groups: standard systemic and targeted. Standard systemic drugs

The Impact of Immune-Modifying Therapy on the Immune Response to COVID-19 Vaccines
There has been longstanding uncertainty and concern over the impact of immune-modifying therapies on the effectiveness of different vaccines; for example, it is well recognised that methotrexate impairs humoral responses to both influenza and pneumococcal vaccines [13]. Since individuals receiving immune-modifying therapies were considered more vulnerable to adverse COVID-19 outcomes than the general population, they have been prioritised during the global COVID-19 vaccine roll-out. Public health policies across the world also advocated an additional COVID-19 vaccine dose as part of the primary course. Therefore, for individuals receiving immunemodifying therapies, a third vaccine dose (BNT162b2 Pfizer/ BioNTech, mRNA-1273 Moderna, or ChAdOx1-S Oxford/ AstraZeneca vaccines) is considered part of the primary vaccination course and this should be administered at least 8 weeks after the second dose [8]. A booster dose is then recommended at least 3 months following the third primary dose.
While data on clinical effectiveness of vaccines (i.e. in prevention of COVID-19 transmission or severe disease) requires longer-term population-level follow-up, the initial focus of the research community turned to the impact of immune-modifying therapies on the immune response to the COVID-19 vaccine, i.e. immunogenicity. The immune response to a vaccine involves a complex interplay between the humoral and cellular immune response; hence when assessing a vaccine's immunogenicity, both humoral and cellular immune responses should be considered [14]. Within the humoral response, seroconversion and neutralising activity can be assessed. Seroconversion is the development of antibodies in the blood serum as a result of vaccination. Following COVID-19 vaccination, seroconversion is assessed by measuring IgG antibodies against the S1 domain of the SARS-CoV-2 S protein. Neutralising antibodies can also be measured which target S1 receptor binding domain (RBD), N-terminal domain (NTD) and S2 region of the S protein. These antibodies block viral entry into host cells by preventing the interaction between the host cell angiotensin-converting enzyme 2 (ACE2) and S protein [15,16]. Finally, assessment of the cellular response to the vaccine involves the analysis of the frequency and function of T cells which recognise viral proteins indirectly and in association with Major Histocompatibility Complex (MHC) I and II molecules [17].

Methods: Literature Search Strategy
We performed a search of PubMed and Google Scholar databases on March 10, 2022, for studies that have investigated the effect of immune-modifying therapy for skin diseases on COVID-19 vaccine responses. Search terms included "immune therapy", "immune-modifying therapy", "immunosuppressant", "vaccines", "COVID-19 vaccines", "COVID-19", "dermatology" and "skin", of which "COVID-19", "COVID-19 vaccines", "immunosuppressants", "vaccines", "skin" and "dermatology" are MESH terms. Outcomes that were analysed included the humoral (seroconversion and/or neutralisation) and cellular responses to the first and second doses of COVID-19 vaccinations. Studies that included individuals with nonskin immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis were included due to shared immunemodifying treatments. There was no minimum size of study and only papers written in English were included.

Immune Response to the 1st Dose of COVID-19 Vaccine
Eight of twenty-five included studies investigated the effects of immune-modifying therapy on the immune response to a first dose of COVID-19 vaccine [18, 20, 22, 24, 32, 33•, 36, 40]. All eight studies evaluated the impact of immune-modifying therapy on seroconversion and one study additionally analysed neutralisation and cellular responses [33•]. Assessment of the serological response to vaccination (i.e. IgG antibody specific to the SARS-CoV-2 S protein) is highly represented due to the accessibility and convenience of the antibody assay.

Seroconversion
The Standard Systemic Immune-Modifying Therapy Methotrexate May Impair Seroconversion Following the First Vaccine Dose More Than Targeted Therapies Such

As TNF Inhibitors
All 8 studies analysing seroconversion following the first vaccine dose showed that individuals who were receiving immune-modifying therapy were less likely to mount a detectable antibody response compared to healthy controls [18, 22, 24, 32, 33, 36 40]

Rituximab Attenuates Seroconversion Following the First Vaccine Dose Compared to Other Immune-Modifying Therapies
Rituximab has a marked effect on seroconversion after the first vaccine dose: Boyarsky et al. found that a lower proportion

Methotrexate Is Associated with Lower Median Neutralisation Titres Following the First Vaccine Dose Compared to Targeted Immune-Modifying Therapy
In our study of neutralisation response to the first dose of COVID-19 vaccine BNT162b2, individuals receiving targeted biologic therapy (TNFi, IL-17i or IL-23i) had similar neutralisation titres against wild-type or Alpha SARS-CoV-2 compared to healthy controls [

Methotrexate or Targeted Immune-Modifying Therapy Does Not Significantly Impair Cellular Responses Following the First Vaccine Dose
Our study also analysed cellular responses, which involved quantifying T cells secreting interferon-γ, IL-2 or IL-21 in response to stimulation with two peptide pools spanning the entire length of the S protein [33•]. Methotrexate or targeted biologics did not impair the cellular response to the first dose of COVID-19 vaccine BNT162b2 as all study groups including the healthy control group showed comparable spike-specific T-cell responses.

Immune Response to the 2nd Dose of COVID-19 Vaccine
Twenty-one studies analysed the effects of immune-modifying therapy on the immune response to two doses of COVID-19 vaccine [19-21, 23, 25-32, 34•, 35-42]. All studies analysed seroconversion following the second vaccine dose. Ten and four studies additionally analysed neutralisation and cellular responses, respectively.

Rituximab Impairs Seroconversion After the Second Vaccine Dose Compared to Other Immune-Modifying Therapies
All studies assessing rituximab showed that a lower proportion of individuals receiving rituximab seroconverted after the second vaccine dose compared to those who were receiving standard systemic or other targeted immune-modifying therapy, or healthy controls (at 2-4 weeks post second vaccine dose) [19-21, 23, 25, 27-32, 33•, 34•, 35-39, 41]. Seroconversion rates in individuals receiving rituximab were as low as 14.3% after the second COVID-19 vaccine [39]. Vaccinations were administered between 1.5 and 12 months after rituximab treatment. The degree of B cell recovery at the time of vaccination correlated with the extent of humoral vaccine response; i.e. a more favourable humoral response was achieved when there was a greater time interval between rituximab treatment and vaccination [27,28]. For example, Furer et al. (n = 86 on rituximab) found that 50% of individuals seroconverted when their vaccination was 1-year after rituximab treatment, compared with less than 20% of those who were vaccinated within 6 months after rituximab treatment [28].

Individuals Receiving Immune-Modifying Therapy Have Lower Spike-Specific IgG Titres Following the Second Vaccine Dose, Compared to Healthy Controls
Individuals receiving immune-modifying therapy had lower titres of spike-specific IgG compared to healthy controls [28,29].  [41]. Despite emerging research on longer-term antibody responses to COVID-19 vaccines in the general population, there remains a paucity of knowledge on the durability of antibody responses in individuals receiving immune-modifying treatment [43]. Data from the general population highlight that the humoral immune response to the second COVID-19 vaccination wanes over time. For example, one study in Estonia involving 122 infection-naïve individuals without significant comorbidities (age range 21-69 years) who were not receiving immune-modifying therapies showed a progressive decline of spike-specific IgG levels at 12 weeks (5226 AU/mL) and 6 months (1383 AU/mL) following the second COVID-19 vaccine [43]. At 6 months after the second vaccine, spike-specific IgG levels were similar to levels in people who had received only one vaccine dose or in those with previous COVID-19 infection (and no vaccination). A largescale UK study of individuals infected with the Omicron variant (n = 86,774), Delta variant (n = 204,154) and uninfected controls (n = 1,572,621) found that 2 vaccine doses (ChAdOx1 nCoV-19 or BNT162b2) were more effective at protecting against symptomatic disease arising from the Delta variant compared to the Omicron variant [44]. Vaccine effectiveness waned rapidly, with limited effects detected after 20 weeks of the second dose of either vaccine. These general population data underscore the importance of subsequent vaccine doses, particularly in the context of newer variants of concern.
Neutralisation Response

The Majority of Individuals Receiving Immune-Modifying Therapy Develop a Neutralising Response After the Second Vaccine Dose
In ten studies where neutralisation was investigated [23, 25-27, 29, 34•, 36, 38, 40, 41], the majority of individuals receiving immune-modifying therapy developed a neutralising response after the second vaccine dose (range 63-100%, with the exception of those receiving rituximab); however, neutralisation titres were lower compared to healthy controls in 3 studies [27,29,38]. Our own study (individuals with psoriasis, n = 67; healthy controls, n = 15) showed that all study participants had detectable neutralising antibodies against wild-type, Alpha and Delta SARS-CoV-2 variants following the second vaccine dose, and there were higher neutralising antibody titres after the second dose compared to the first [ In contrast, in a smaller study (n = 14), Seree-aphinan et al. found that individuals receiving azathioprine, ciclosporin, mycophenolate mofetil or moderate-to-high dose corticosteroids monotherapy had a lower neutralising response compared to those who received low dose methotrexate or low dose systemic corticosteroids or biologics [38].

Rituximab Impairs Neutralisation Responses to the Second Vaccine Dose Compared to Other Immune-modifying Therapies
Patients receiving rituximab were less likely to develop detectable neutralising antibodies after the second vaccine dose compared to controls or those receiving other immune-modifying therapies. For example, Deepak et al. (individuals with IMIDs, n = 133; healthy controls, n = 53) found that neutralisation titres in individuals with IMIDs (including RA, spondyloarthritis, uveitis, SLE, vasculitis, Sjogren syndrome, multiple sclerosis and IBD) who were receiving anti-CD20 therapy were lower compared with those who were not receiving anti-CD20 therapy (half-maximal dilution titres 723 vs 2445, respectively) [27].

Methotrexate May Impair the Cellular Immune Response to the Second Vaccine Dose
In comparison to data available on humoral responses, there is a relative paucity of data on cellular immune responses to the COVID-19 vaccine [45]. This represents an important knowledge gap because studies indicate that a robust cellular response is critical in the protection against severe COVID-19 by enabling accelerated viral clearance [17]. SARS-CoV-2-specific T cell responses may help to prevent infection and may also support the development of robust immunological memory since CD4 spike-specific T cell responses promote antibody generation, with follicular helper T cells correlating with long-term/durable humoral immunity [45]. Furthermore, unlike humoral responses, which seem to be evaded by many variants of concern, cellular responses seem to show stronger cross-protection highlighting their importance in the face of ongoing viral evolution [46].
The four studies identified in this review that investigated cellular responses in individuals receiving immune-modifying therapy yielded broadly similar findings [

Timing of Immune Response Readout Relative to Vaccination
The majority of studies in this review analysed immune responses to COVID-19 vaccines at 2 to 6 weeks following the first or second dose of the vaccine (Table 2). A smaller number of studies analysed immune responses at 7-8 days [19,29] or up to 10 weeks following the second dose [31,32].

Immune Response to Different SARS-CoV-2 Variants
Of twenty-five studies included in this review, only four analysed the immune response against different SARS-CoV-2 variants [25, 26, 33•, 34•]. Dailey et al. (n = 33) found similar neutralising antibody responses following vaccination in an IBD population against wild-type and Alpha variants [26]. Our studies analysed neutralising activity against wild type, Alpha and Delta variants [33•, 34•]. Neutralising activity against wild-type SARS-CoV-2 was significantly lower after the first vaccine dose in patients receiving methotrexate compared to controls, but was preserved in those receiving targeted biologics. Neutralising titres against the Alpha variant were similarly low in all study participants [33•]. We subsequently found that neutralising antibody titres against wild-type, Alpha and Delta SARS-CoV-2 variants following the second vaccine dose were similar in patients receiving methotrexate, targeted biologics, and healthy controls [34•]. Chen et al. (individuals with IMIDs, n = 75; healthy controls, n = 25) also found no statistically significant differences in antibody responses in their IMID cohort against wild type, Alpha, Beta and Delta variants at 3 months following a second dose of vaccine [25]. Importantly, there remains a paucity of data on newer variants of concern. This remains an area of active investigation since the impact of a lower titre antibody vaccine response in the context of immunemodifying therapy is likely to be exacerbated when considering protection against newer variants such as Omicron [44].

Omission of Immune-Modifying Therapy Around the Time of Vaccination
Prior studies found that temporary discontinuation of methotrexate for 2-4 weeks after seasonal influenza vaccination in patients with rheumatoid arthritis led to greater antibody titres [47,48]. There has thus been active investigation into whether the omission of methotrexate doses around the time of COVID-19 vaccination is beneficial. The VROOM trial was a UK open-label two-arm parallel-group multicentre (n = 26 sites) randomised controlled superiority trial studying the effects on COVID-19 booster vaccine responses of temporarily suspending methotrexate for 2 weeks post-vaccination versus continued methotrexate [49•]. The study included 254 adults with IMIDs (127 in the 'continue methotrexate' group and 127 in the 'suspend methotrexate' group). Their mean age was 59 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the mean S1-RBD antibody titre was 22,750 U/mL (95% CI 19,314-26,796) in the 'suspend methotrexate' group versus 10,798 U/mL (95% CI 8970-12 997) in the 'continue methotrexate' group (geometric mean ratio 2·19, 95% CI 1·57-3·04; p < 0·0001). Thus, a 2-week interruption of methotrexate treatment post-booster vaccine may lead to increased vaccine efficacy and greater duration of protection [49•]. A greater proportion of participants in the 'suspend methotrexate' group self-reported at least one disease flare in the first 4 weeks post-vaccination compared to the 'continue methotrexate' group (56% vs 31%); however, most flares were selfmanaged in both groups. Further research into the temporary suspension of other standard and targeted immune-modifying drugs around the time of vaccination is warranted.

Total Number of Vaccine Doses
While there remains a paucity of data on the immune response to more than two COVID-19 vaccine doses, there are emerging reports. For example, Schmiedeberg et al. (n = 17) found that individuals with rheumatoid arthritis who were receiving standard systemic and/or targeted immune-modifying therapy who had not seroconverted after the first two COVID-19 vaccine doses mounted a significant antibody response following the third dose [50]. Wieske et al. showed that a third vaccine dose successfully boosted seroconversion rates in individuals receiving mycophenolate mofetil combination treatments, from 52.6% after the second vaccination to 89.5% after the third [41]. However, the study found that use of anti-CD20 biologics continued to impair humoral responses, with seroconversion rates of 36.9% and 45.6% after the second and third vaccine doses, respectively [41]. In further support, Simon et al. found that while a third vaccine enabled seroconversion in some individuals on rituximab who had not responded to previous vaccine doses, seroconversion rates remained lower in this group compared to previous non-responders who were not receiving rituximab (6/33 [18.2%] vs 26/33 [78.8%], respectively) [51].
With respect to clinical effectiveness, a study by Shen et al. using electronic health records in the Michigan Medicine US healthcare system (n = 154,519) found that individuals receiving immune-modifying drugs (standard systemic and/or targeted immune-modifying therapy) who had a third vaccine dose had a lower incidence of SARS-CoV-2 infection compared to those who did not have a third dose [52 •]. Immune responses were not studied. Additionally, Risk et al.'s analysis of Michigan Medicine data (n = 168,414) indicated that three doses of BNT162b2 or mRNA-1273 vaccine was strongly protective against COVID-19-related hospitalisation in both individuals receiving immunemodifying therapy (vaccine effectiveness 87%, 95% CI 74-93) and those who were immunocompetent (92%, 95% CI 87-95) [53]. Further large-scale clinical effectiveness data from populations receiving immune-modifying therapies are awaited.

Conclusions
SARS-CoV-2 has had a devastating effect around the world, with vaccinations being paramount in the public health strategy against COVID-19. While vaccination programmes have seen great success, there are still limited data on the clinical effectiveness of these vaccines in the global population who are receiving treatment with immune-modifying drugs, including those with skin IMIDs [54].
Research to date indicates that while individuals receiving immune-modifying therapy are more likely to have attenuated humoral responses to a single dose of COVID-19 vaccine compared to healthy controls, this may be improved by a complete course of vaccination. Hence, individuals receiving immune-modifying treatments should be encouraged to take up a complete vaccine course to mitigate their risk against severe COVID-19 outcomes [55]. Of specific note are B cell targeted biologics such as rituximab, which markedly impair the humoral response to both the first and second COVID-19 vaccination. Although this remains an area of active research, the impact of rituximab on vaccine responses may be improved by increasing the time interval between the rituximab treatment and vaccination [56]. Clinicians should also consider temporary cessation of methotrexate following vaccination given the emerging trial data [49 •].
There remains a paucity of data on cellular immune responses, with the few available studies indicating lower responses to two vaccine doses in individuals receiving immune-modifying therapies compared to healthy controls, which may impact the durability of immune responses. Research in large patient populations on the longevity/kinetics of the complex humoral and cellular response to subsequent vaccine doses, including against newer variants of concern, is now warranted, in addition to data on immune correlates of vaccine clinical effectiveness.
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