Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies
Abstract
:1. Introduction
2. COVID-19 Vaccines
Vaccines | Composition | Cellular Immunity | Neutralizing Antibodies | Doses | Efficacy | References |
---|---|---|---|---|---|---|
Pfizer Comirnaty | 30 µg mRNA Spike | Yes | Yes | 2, 3 weeks apart | 95% | [28] |
Moderna Spikevax | 100 µg mRNA Spike | Yes | Yes | 2, 4 weeks apart | 94.1% | [29] |
AstraZeneca Vaxzevria | Non-replicating viral vector Spike DNA | Yes | Yes | 2, 4–12 weeks apart | 70% | [21,22] |
Janssen (J&J) | Non-replicating viral vector Spike DNA | Yes | Yes | 1 | 73–82% at 14–28 days, respectively | [23,24] |
Cansino Biological Inc. | Non-replicating viral vector Spike DNA | Yes | 1 | [25] | ||
Sinovac CoronaVac | Inactivated whole virus | Yes | 2, 2 weeks apart | 83.5% | [30,31] | |
Gamaleya Res. Institute | Non-replicating viral vector Spike DNA | Yes | 2, 3 weeks apart | 91.6% | [26,27] | |
BBV152 Bharat Biotech | Inactivated whole virus | Yes | 2, 2 weeks apart | [32,33] | ||
Novavax | Recombinant Spike+ Adjuvant | Yes | Yes | 2, 3 weeks apart | 89.7% | [19,20] |
3. Safety of COVID-19 Vaccines in Patients with AIAIDs, PIDs, and SIDs
4. Immunosuppressive/Immunomodulating Therapy and COVID-19 Vaccines
5. Should Patients with AIAIDs, PIDs, and SIDs Be Prioritized in the Access to Vaccines?
6. Recommendations
- Anti-COVID-19 mass vaccination has personal and social benefits. Preventing the disease in single individuals may allow easier achievement of herd immunity, which is needed to interrupt the viral spread and protect individuals who cannot be vaccinated.
- Vaccinations are a safe and effective tool for prevention and control of infectious diseases. Patients with AIAIDs, PIDs, and SIDs are at higher risk of infections, including those by SARS-COV-2. Few studies have addressed the issue of anti-COVID vaccination in these patients, but many are available on the safety, immunogenicity, efficacy, and possible contraindications of traditional vaccines in AIAIDs, PIDs, and SIDs patients. These studies may represent the basis on which to recommend the anti-COVID-19 vaccines [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15] (Table 1, Table 2 and Table 3)
- The vaccine is more effective the lower the immunosuppression; however, the risk of a flare-up of the underlying disease after the interruption of an immunosuppressive drug is real, thus, in general, no modification of immunosuppressive therapy either during or following vaccination is advisable. In particular cases, according to the clinical picture and the drugs used, modifications and/or discontinuations of immunosuppressive therapy may be recommended by the immunology specialist.
- In general, inactivated vaccines or vaccines containing non-infectious viral sequences may be safely administered to patients with AIAIDs, PIDs, and SIDs in clinical remission [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15] (Table 1, Table 2 and Table 3). Anti-COVID-19 vaccines of the traditional type that are composed by inactivated virus [31,32,33] or recombinant Spike protein and adjuvant [19], for which wider scientific knowledge and clinical experience are available, could preferentially be indicated in patients with AIAIDs, PIDs, and SIDs; however, no traditional vaccines are approved by the European Medicines Agency (EMA) yet (Table 4).
- Viral vector non-replicating anti-COVID-19 vaccines, such as the ones from AstraZeneca (Vaxzevria) [21,22], Janssen/Johnson & Johnson [23,24], Cansino Biological Inc. [25], and Gamaleya Research Institute [26,27] (Table 2), are known based on application to the anti-Ebola vaccine, however our knowledge of them is very limited. One problem with these vaccines is the previous and effective anti-viral vector immune response, which may totally inactivate the vaccine; however, this problem involves the general population, not only patients with AIAIDs, PIDs, and SIDs, and may be reduced by using viral vectors from primates. Although during the registration studies substantial safety of these vaccines has been observed [21], lack of patients with AIAIDs, PIDs, and SIDs in these studies does not allow definitive conclusions about the safety and efficacy of these vaccines in these patients. Moreover, recently the discovery of very rare, but severe and often lethal, cases of VITT prompted the regulatory agencies of many countries to substantially limit the use of these vaccines.
- Anti-COVID-19 mRNA vaccines, such as those developed by Pfizer/Biontech [28] and Moderna [29], are brand new and the first ones to be used on a large scale. During the pre-approval studies, after four months of observation, the groups treated with the two vaccines showed an efficacy of 95% and 94.1%, respectively, compared to the group of subjects who had received placebo, and the safety was considered optimal (Table 4) [28,29]. The mRNA vaccine effectiveness has also been calculated at 91% and 81% after the complete vaccine cycle or only the first dose, respectively [126]. Although in the pre-approval studies details on the possible presence of patients with AIAIDs in the study population have not been provided, recent studies have reported substantial safety and immunogenicity of these vaccines in patients with AIAIDs [48,49,50,92,106,107,108]. Even in PIDs, two preliminary studies [98,99] have shown the substantial safety and immunogenicity of the mRNA vaccines. Finally, COVID-19 vaccines were safe and immunogenic in onco-hematologic pathologies, and mRNA vaccines were more immunogenic than the adenoviral vaccine [101]. Despite the absence of currently released definitive recommendations, the cited preliminary studies confirm that mRNA vaccines seem to be well tolerated in patients with AIAIDs, PIDs, and SIDs. In the general population as well, mRNA vaccines show a very low frequency of serious adverse events, lower than those observed in vectored vaccines. The Task Force believes that, based on the data reported above, mRNA vaccines should be chosen for use in clinically stabilized patients with AIAIDs, PIDs, and SIDs.
- There is no general agreement regarding priority criteria for anti-COVID vaccine access for patients with AIAIDs, PIDs, and SIDs, because there is no consensus on their actual risk of infection or developing a more serious disease. The best criterion to evaluate the priority level of access to COVID-19 vaccine in these patients is the clinical one [124]: in patients with AIAIDs under heavy immunosuppressive therapy and a history of serious and recurrent infections, the immunology specialist should determine the priority level, in keeping with the Raccomandazioni ad interim sui gruppi target della vaccinazione anti-SARS-CoV-2/COVID-19 (GURI 24.3.2021), elaborated by the Italian Ministry of Health. Clinical criteria should guide the management of patients with PIDs and SIDs as well. For these patients, vaccination of cohabiting relatives and healthcare providers is recommended.
- The Task Force does not consider it appropriate to interrupt/discontinue immunosuppressive therapy, excepting for high dosage CCS (≥10 mg of prednisone-equivalent [104]) and anti-CD20 mAbs, such as rituximab [103,104,105] (Table 6). Moreover, in the case of MTX [105,106], abatacept [105,106], JKI [105,106], and mycophenolate [106], the immunology specialist will evaluate the possible discontinuation based on the patients’ clinical characteristics. Regarding PIDs, the risk of non-response should be evaluated, especially in severe combined and humoral immunodeficiencies. In the case of non-response passive immunotherapy with mAbs or convalescent plasma, vaccination should carefully be considered.
- The patient’s immunology specialist should be continuously updated and available for evaluating the vaccination risk level (disease activity and immunosuppression consequent to the current therapy) of the patient. The specialist should be continuously informed and able to provide all information useful for handling treatment during the vaccination period.
- In keeping with the activity of the Italian Drug Agency (AIFA) to inform the whole population, the three Italian Immunological Societies will make available all data coming from studies carried out on immunized populations as soon as possible, using the sites or the traditional communication channels available to the members of scientific societies and the patient associations.
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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AIAIDs | Corticosteroids | IVIg/scDMARDs | bDMARDs/tsDMARDs | Inactivated Vaccines | Live Vaccines |
---|---|---|---|---|---|
High doses: ≥20 mg/day prednisone-equivalent for 1–2 weeks; non immunosuppressive doses: 7.5 mg/day | Sulphasalazine, hydroxichloroquine, azathioprine, mycophenolate, methotrexate, leflunomide, cyclosporine, tacrolimus, cyclophosphamide | infliximab, adalimumab, etanercept, golimumab, certolizumab, rituximab, tocilizumab, abatacept, anakinra, canakinumab, belimumab, secukinumab, ixekizumab, ustekinumab, tofacitinib, baricitinib | Hepatitis A/B, human papillomavirus, influenza, herpes zoster, inactivated poliovirus, pneumococcus, tetanus/diphtheria/pertussis, polysaccharide typhoid fever, Hib, meningococcus | Measles/Mumps/Rubella, Varicella, BCG, Ty21A, Yellow fever | |
Rheumatoid arthritis, Systemic lupus, erythematosus Sjögren Syndrome, Anti-phospholipid syndrome, Systemic sclerosis, Polymyositis/ dermatomyositis, Vasculitis, Psoriatic arthritis, Spondyloarthritis, Familiar Mediterranean Fever, Periodical fever syndromes, Type 1 diabetes, Inflammatory bowel diseases, Multiple sclerosis | At high doses, they seem to interfere with the immune response to vaccines. Combination steroids/anti-TNF-α is particularly associated with the infection risk [10]. | IVIg should not be administered together with live vaccines due to the risk of vaccine inactivation [11], or with an inactivated vaccine because evaluating vaccine immunogenicity become simpossible. csDAMRDs are generally well tolerated at the doses generally used in IMIDs and they do not seem to interfere with the immune response. For methotrexate, a negative interference with the pneumococcal vaccine has been described, which has not been confirmed with the conjugate vaccine [12]. | When used alone, they are well tolerated and do not induce immunosuppression; immunosuppression is induced when they are used in combination. Abatacept and tofacitinib have been associated with a slightly reduced response to influenza and pneumococcus vaccines. Rituximab markedly reduces antibody response, but it does not seem to modify the adaptive cellular one [13]. Vaccination should be carried out before starting therapy with rituximab; in case of impossibility, it should be carried out 6 months after the last infusion of rituximab and 1 month before the next one. | Generally allowed, influenza and pneumococcus recommended, and, in particular subjects, hepatitis B, papillomavirus and herpes zoster. | Generally contraindicated, Measles/Mumps/Rubella seems well tolerated. Caution for Yellow fever, even though a recent review seems to partially reduce these fears [14]. |
PIDs | Corticosteroids | IVIg/SCIg | HSCT/Gene therapy | Inactivated Vaccines | Live Vaccines |
---|---|---|---|---|---|
High doses: ≥20 mg/day prednisone-equivalent for 1–2 weeks; non immunosuppressive doses: 7.5 mg/day | Hepatitis A/B, human papillomavirus, influenza, herpes zoster, inactivated poliovirus, pneumococcus, tetanus/diphtheria/pertussis, polysaccharide typhoid fever, Hib, meningococcus, | Measles/Mumps/Rubella, Varicella, BCG, Ty21A, Yellow fever | |||
Major antibody defects (XLA, CVID) Minor antibody defects (Defect of: IgA, IgG subclasses, specific antibodies) SCID—CID MSMD Invasive bacterial infections CMCD Defects of TLR Defects of IL12/IFN-ɣ pathway Defects of complement Congenital phagocyte defects Complete DiGeorge Syndrome Partial DiGeorge Syndrome Ataxia-Telangiectasia Wiskott-Aldrich Syndrome Hyper-IgE Syndrome IPEX Syndrome APECED Syndrome | At high doses, they seem to interfere with the immune response to vaccines. | IVIg should not be administered together with live vaccines due to the risk of vaccine inactivation [11], or with an inactivated vaccine because evaluating vaccine immunogenicity becomes impossible. | After 1 year following engraftment and lack of GVHD, it is possible to set the vaccination schedule with inactivated vaccines. Live vaccines should not be set before 2 years from transplant [15]. | Generally allowed in all the PIDs, excepting SCID and complete DiGeorge syndrome, in which only the polysaccharide vaccines (meningococcus, pneumococcus, Hib) are allowed. | Generally contraindicated, MMR and Varicella seem well tolerated in the minor antibody defects, complement defects, congenital phagocyte defects, partial DiGeorge syndrome, ataxia-telangiectasia, and hyper-IgE syndrome. Caution should be used for Yellow fever vaccine. |
SIDs | Corticosteroids | IVIg/SCIg | Chemotherapy/Biologics/Janus Kinase Inhibitors | Inactivated Vaccines | Live Vaccines |
---|---|---|---|---|---|
High doses: ≥20 mg/day prednisone-equivalent for 1–2 weeks; non immunosuppressive doses: 7.5 mg/day | Hepatitis A/B, human papillomavirus, influenza, herpes zoster, inactivated poliovirus, pneumococcus, tetanus/diphtheria/pertussis, polysaccharide typhoid fever, Hib, meningococcus | Measles/Mumps/Rubella, Varicella, BCG, Ty21A, Yellow fever | |||
Transplanted patients Hematological patients Oncological patients Patients with IMIDs on immunosuppression Dialysis patientsSevere asthma/COPD Splenectomized patients HIV-infected patients | At high doses they seem to interfere with the immune response to vaccines. | IVIg should not be administered together with live vaccines due to the risk of vaccine inactivation [11], or with an inactivated vaccine because evaluating vaccine immunogenicity becomes impossible. | In case of high-level immunosuppression by chemotherapy in onco-hematological pathologies, inactivated vaccines should preferably be administered either before or after, but not during, the treatment. | Generally allowed in all the reported SIDs. Polysaccharide vaccines (pneumococcus, meningococcus, Hib) are specifically recommended in the splenectomized patients. Polysaccharide and influenza vaccines are recommended in transplanted patients and in the other SIDs. Hepatitis A and B in liver transplanted patients. Hepatitis B in HIV-infected patients. Two months after the transplant it is possible to plan vaccinations with inactivated vaccines [7]. In Rituximab-treated patients, vaccination should be carried out at least 6 months after the last infusion. | Generally contraindicated, Measles/Mumps/Rubella and Varicella are allowed in HIV-infected patients, provided that they have CD4 ≥ 200/µL. Caution for Yellow fever, even though a recent review seems to partially reduce these fears [14]. |
WHO Label | Lineage | Country of Isolation | Transmissibility | Disease Severity | Vaccine Protection |
---|---|---|---|---|---|
Alpha | B.1.1.7 | United Kingdom | Increased | Increased | Unmodified |
Beta | B.1.351 | South Africa | Increased | Increased | Reduced |
Gamma | P.1 | Brazil | Increased | Increased | Reduced |
Delta | B.1.617.2 | India | Increased | Increased | Reduced |
Drug | Modification of Therapy | Modification of Therapy in Relation to Vaccination |
---|---|---|
Hydroxychloroquine | NO | |
Apremilast | NO | |
IVIG | NO | |
Glucocorticoids (Prednisone-equivalent < 10 mg/day) | NO | |
Glucocorticoids (Prednisone-equivalent ≥ 10 mg/day) | The dose should be reduced to <10 mg/die, if possible, before each vaccine dose | |
Sulphasalazine | NO | |
Leflunomide | NO | |
Mycophenolate mofetil | Delay the dose, if >20 mg/week, for 1 week for each vaccine dose, in case of stable disease * | |
Azathioprine | NO | |
Cyclophosphamide (Oral) | NO | |
TNFα inhibitors (Adalimumab, Infliximab, Golimumab, Certolizumab, Etanercept) | NO | |
Anti-IL-6R moAb (Tocilizumab) | NO | |
IL-1β inhibitors (Anakinra, Canakinumab) | NO | |
Anti-IL-17A moAbs (Secukinumab, Ixekizumab) | NO | |
Anti-IL-12/23 moAb (Ustekinumab) | NO | |
Anti-IL-23 moAbs (Tildrakizumab, Guselkumab, Risankizumab) | NO | |
Anti-Blys moAb (Belimumab) | NO | |
Calcineurin inhibitors (oral) | NO | |
Methotrexate | Delay the dose, if >20 mg/week, for 1 week for each vaccine dose, in case of stable disease * | |
JAK inhibitors | Delay the dose for 1 week for each vaccine dose * | |
Abatacept sc | Temporary interruption 1 week before and 1 week after each vaccine dose * | |
Abatacept iv | Each vaccine dose should be administered 4 weeks after the last infusion and the next infusion should be postponed 1 week * | |
Cyclophosphamide iv | The infusion should be administered 1 week after vaccine * | |
Anti-CD20 moAb (Rituximab) | The first vaccine dose should be administered 4 weeks before the next scheduled cycle. Rituximab may be administered not before 3 weeks after the second vaccine dose, provided that the patient’s clinical condition allows. |
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D'Amelio, R.; Asero, R.; Cassatella, M.A.; Laganà, B.; Lunardi, C.; Migliorini, P.; Nisini, R.; Parronchi, P.; Quinti, I.; Racanelli, V.; et al. Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies. Biomedicines 2021, 9, 1163. https://doi.org/10.3390/biomedicines9091163
D'Amelio R, Asero R, Cassatella MA, Laganà B, Lunardi C, Migliorini P, Nisini R, Parronchi P, Quinti I, Racanelli V, et al. Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies. Biomedicines. 2021; 9(9):1163. https://doi.org/10.3390/biomedicines9091163
Chicago/Turabian StyleD'Amelio, Raffaele, Riccardo Asero, Marco Antonio Cassatella, Bruno Laganà, Claudio Lunardi, Paola Migliorini, Roberto Nisini, Paola Parronchi, Isabella Quinti, Vito Racanelli, and et al. 2021. "Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies" Biomedicines 9, no. 9: 1163. https://doi.org/10.3390/biomedicines9091163