Vaccination in rheumatic diseases

Patients with autoimmune inflammatory rheumatic diseases (AIIRD) are at higher risk for serious infections due to underlying immune dysfunction, treatment-associated immunosuppression or both.1–3 Although these patients should receive the recommended vaccines, the vaccine coverage in this population remains suboptimal.4 5 Factors contributing to vaccination hesitance include concerns about disseminated infections from live-attenuated vaccines, the potential risk of exacerbating underlying autoimmune diseases and uncertainties surrounding vaccine efficacy in patients with immunosuppressed AIIRD.6–10 In this context, the novel mRNA vaccine platform has emerged as a promising solution, providing new vaccines with potentially improved efficacy and safety.11

Structure of mRNA vaccines

Instead of using preformed antigens, messenger RNA (mRNA) vaccines introduce mRNA-encoding antigenic proteins into host cells12 (figure 1). Within these cells, the target antigens are synthesised, processed and presented to immune cells, closely mimicking the immune response triggered by a viral infection.13 14 mRNA vaccines comprise two key components: antigen-encoding mRNA and a delivery system. Non-self mRNAs, like viral RNAs, are detected by intracellular nucleotide sensors, such as toll-like receptor (TLR) 7, retinoic acid-inducible gene-I (RIG-1) and anti-melanoma differentiation-associated gene (MDA)-5, initiating a cellular antiviral response that can hinder protein synthesis and degrade nucleic acids to suppress the production of viral particles.15 16 Consequently, vaccine mRNA, being non-self, is eliminated before it can be translated into antigenic proteins. Modifying mRNA such as substitution of uridine with pseudouridine reduces TLR activation, thereby bypassing host antiviral response.17 18 This modification also enhances the biological stability and translational capacity of mRNA, marking a pivotal milestone in the feasibility of mRNA vaccines and mRNA-based cancer and gene therapy, which was acknowledged with a Nobel Prize in Physiology and Medicine in 2023.19 20 Further mRNA editing techniques, including methylpseudouridine, 5’ capping, tailing and codon optimisation (eg, point mutations), have significantly improved mRNA stability and the expression of target antigens.21 22

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Figure 1

Mechanism of mRNA vaccines. (A) mRNA vaccines consist of lipid nanoparticle as a vehicle that carries mRNA. mRNA vaccine is given as an intramuscular injection; (1) after injection, mRNA is taken up by host cells via endocytosis. (2) mRNA is released from the endosome into the cytoplasm; (3) mRNA is translated by ribosomes into antigenic proteins; (4) antigenic proteins are secreted and then be taken up by to local antigen-presenting cells, including dendritic cells (DCs). (5) DCs are trafficked to lymph nodes where they activate CD4+ and CD8+ T cells; (6) CD4+T cells differentiate into Tfh cells or Th1 cells; CD8+T cells become circulating cytotoxic T cells; Tfh cells prime B cells to differentiate into antibody-secreting plasma cells. Vaccine mRNAs are recognised by intracellular nucleotide sensing receptors, such as (a) TLR and (b) RIG-I/MDA-5, triggering a type I IFN response. (B) Antibody response following mRNA vaccines. IFN, interferon; IRF, interferon regulatory factor; LPN, lipid nanoparticle; MAVS, mitochondrial antiviral-signalling protein; MDA, melanoma differentiation-associated gene; MHC, major histocompatibility complex; mRNA, messenger RNA; RIG-I, retinoic acid-inducible gene-I; Tfh, follicular helper T cell; Th, helper T cell; TLR, toll like receptor.

An efficient delivery vehicle protects mRNA from degradation by ubiquitous RNases and ensures effective cellular entry and release.23 The most advanced delivery system is lipid nanoparticles (LNPs).24 LNPs consist of an ionisable or cationic lipid that interacts with the polyanionic RNA, a helper phospholipid supporting the bilayer structure, a cholesterol analogue adjusting the fluidity of the lipid bilayer and a polyethylene glycol (PEG)-lipid enhancing colloidal stability while reducing opsonisation. LNPs are engineered to fuse with the target cell surface and to form endosomes. A pH change within the acidic endosome facilitates the release of mRNA into the cytosol, where they are translated into antigenic proteins by cytosolic ribosomes.25

Advantages of mRNA vaccine

mRNA vaccines present several key advantages over other vaccine classes (box 1). As non-live vaccine, they do not produce infectious particles, eliminating the possibility of vaccine-induced infection, even in severely immunocompromised patients. Live-attenuated vaccines including Measles, Mumps and Rubella, varicella, yellow fever and polio are contraindicated for immunosuppressed patients due to the potential risk of life-threatening disseminated infections, while Zostavax, a live-attenuated herpes zoster (HZ) vaccine can be administered to patients receiving low-to-moderate immunosuppression.4 26 However, determining the thresholds for moderate and high immunosuppression remains arbitrary, largely based on expert opinions due to the lack of robust clinical trial data. This is further complicated by the emergence of novel biological and synthetic disease-modifying antirheumatic drugs such as Janus kinase (JAK) inhibitors, Tyk inhibitors and granulocyte macrophage-colony stimulating factor inhibitors, with uncertain extent of immunosuppressive effect.27 28 In this regard, mRNA vaccines with no risk of infection would provide a safer alternative than live vaccines for patients taking any immunosuppressants.

mRNA vaccines elicit an immune response closely resembling natural viral infections, inducing robust and durable cellular and humoral immunity.13 14 The manipulation of nucleotide sequence allows for fine-tuning of vaccine immunogenicity. Self-amplifying RNAs, which are replicated by host cellular machinery, enhance the production of antigenic proteins, allowing for reduced vaccine dosing and so vaccine side effects.29 30 The limited biological half-life of mRNA ensures complete clearance from the body after sufficient antigen expression, minimising any long-term effects.31 Unlike viral-vector vaccines, LNP carrier do not induce a host immune response against the carrier itself. Adenoviral vector-based COVID-19 vaccines, where host immune response could potentially neutralise the vectors during subsequent vaccinations, can reduce mRNA delivery and accordingly vaccine efficacy.32 Importantly, mRNA does not integrate with the host DNA, eliminating the risk of insertional mutagenesis and cancer risk.

The most significant advantage of mRNA vaccines is the concept of ‘plug and play’. Once the genetic sequence of any target antigen is known, mRNA can be swiftly designed, synthesised and assembled into LNP vehicles. This enables the timely development of new vaccines against emerging infectious diseases, such as Zika infection,33 or adapting current vaccines to rapidly evolving pathogens like COVID-19 and influenza viruses. Multiple mRNAs can be combined in a single combination vaccine to target various pathogens or create multiple antigens from a single pathogen, enhancing vaccine efficacy.24 Finally, mRNA vaccines offer remarkable manufacturing advantages. They can be rapidly and efficiently produced in a cell-free environment, facilitating swift, scalable and cost-effective production.34 Therefore, the rapid response potential of mRNA vaccine platforms along with cost-effect production is well-suited to efficiently respond to future epidemics and pandemics.

Inbuilt adjuvants and immune activation

Both mRNA and LNP possess inherent adjuvant properties.35 36 mRNA is detected by intracellular innate immune sensors, such as cytosolic RIG-1/MDA-5 and endosomal TLR, which stimulate the production of type 1 interferon and proinflammatory cytokines interleukin (IL)-1β and IL-614 (figure 1). These cytokines boost vaccine response while also triggering local and systemic inflammation, observed in 70–80% of COVID-19 vaccine recipients in a dose-dependent manner.37–39 Fine-tuning innate immune activation through modification of mRNA and carrier may optimise the efficacy and safety of mRNA vaccines.18

Lessons learnt from COVID-19 pandemics

The COVID-19 pandemic accelerated the realisation of a long conceptual vaccine platform. Pfizer and Moderna’s mRNA vaccines emerged as the recommended strategy against SARS-CoV-2, demonstrating remarkable efficacy and safety for hundreds of millions globally over the past 2 years.40 First-generation SARS-CoV-2-COVID-19 vaccines were developed within weeks of publication of the full-length Wuhan strain spike protein sequence with the first clinical trial initiated just 4 months after virus isolation.41 42 Within 11 months of the RNA sequence publication, emergency use authorisation was granted for Pfizer and Moderna vaccines, with approximately 90% efficacy demonstrated in phase 3 studies. This efficacy was shown to fade over time, leading to the recommendations for booster vaccinations roughly every 6 months for 2 years.43 However, these vaccines have been shown to produce robust long-term humoral and cell-mediated immunity and provide protection against severe COVID-19 despite waning neutralising antibody titres.44

The emergence of COVID-19 variants posed challenges to vaccine efficacy. Bivalent or multivalent vaccines like mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech), targeting both Omicron BA.4–BA.5 and the ancestral wild-type spike, as well as the new monovalent mRNA vaccines targeting Omicron XBB1.5 subvariant, theoretically could have enhanced vaccine effectiveness. This rapid adaptation underscores the advantage of mRNA vaccine technology in combating rapidly changing pathogens.45–47

Risks of mRNA vaccines

A large-scale vaccination campaign during the COVID-19 pandemic demonstrated a good safety profile. Nevertheless, sporadic reports of infrequent yet significant adverse events have contributed to vaccine hesitancy (table 1). Mild anaphylactic reactions have been documented in 2.5 cases per million vaccinations with the Moderna vaccine and 2.2 cases per million for the Pfizer-BioNTech vaccine.37 48 This incidence appears to exceed that associated with traditional vaccines.49 PEG allergy has been estimated at 0.15 cases per million person-years in the USA and Canada, implying that other vaccine components contribute to anaphylaxis.50 51 Interestingly, pre-existing antibodies against PEGylated lipids, are present in approximately 40% of the general population, suggesting that anti-PEG antibodies are not the sole causative factor.52 The Centers for Disease Control and Prevention recommends that individuals with a history of anaphylactic reactions to mRNA vaccines avoid them.

A small fraction (0.125%) of mRNA-vaccinated individuals experienced severe immune-mediated adverse effects, encompassing a range of conditions such as acute myocardial infarction, Bell’s palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis (more prevalent among younger age groups), pulmonary embolism, stroke, thrombosis with thrombocytopenia syndrome, lymphadenopathy, appendicitis, HZ reactivation, neurological complications and autoimmunity.53

mRNA vaccines in patients with AIIRD

COVID-19 vaccination in autoimmune diseases study, an international collaborative study involving 167 collaborators from 110 countries, demonstrated a safety profile for COVID-19 vaccines in patients with AIIRD comparable to that of the general population.54–56 However, the flare rate of AIIRD following vaccination ranged from 10% to 37%.57 58 In the COVAX physician-reported registry including 5121 participants across 30 countries, flares were reported in 4.4% of cases, with 0.6% of severe cases.59 In summary, although disease flare is not uncommon, severe flares are rare. Immunosuppressant medications (corticosteroids, methotrexate, abatacept, mycophenolate mofetil and JAK inhibitors) can diminish vaccine immunogenicity and presumably efficacy.60 Further optimisation of mRNA and LNP formulation may mitigate the flare risk and simultaneously enhance vaccine efficacy in patients with AIIRD.

During the COVID-19 pandemic, new AIIRD cases, including inflammatory arthritis, connective tissue disease, systemic vasculitis, were reported after vaccination or infection.61–64 Further investigation is warranted to determine whether preclinical autoimmune diseases manifest clinically or whether they are triggered by the COVID-19 vaccine or infection.

mRNA vaccines in development

This mRNA vaccine technology, validated through the success of the COVID-19 experience, drives the development of mRNA vaccines for other indications. Dozens of new vaccines are currently in phase 1–3 clinical trials, most notably targeting easily communicable respiratory pathogens. Here, we summarised the current mRNA vaccine development tailored to the needs of patients with AIIRD (tables 2 and 3).

Respiratory syncytial virus

Respiratory syncytial virus (RSV) infection can progress into lower respiratory tract disease with a significant morbidity in older adults and particularly those who are immunosuppressed or with other comorbidities (eg, cardiovascular or pulmonary disease).74 It reached epidemic proportions in 2022.75

RSV uses the highly conserved fusion (F) protein to enter the host cells. On encountering a target cell, the prefusion F protein transforms rapidly into elongated postfusion conformation, concealing the primary target of neutralising antibodies. Therefore, neutralising antibodies must bind to the prefusion F protein to block cell entry. The 1960s formalin-inactivated RSV vaccine proved unsuccessful because formalin inactivation triggers postfusion conformation change; the vaccine generated antibodies failed to neutralise the infectious prefusion F protein.76 mRNA engineering enables the synthesis of more stable F protein in the prefusion state.77 Recently two subunit RSV vaccines targeting prefusion F proteins have been approved. AS01E-adjuvant (Arexvy) and the non-adjuvanted (Abrysvo) RSV had an efficacy of 82.6% and 67%, compared with placebo, respectively.78 79 Currently, there are several mRNA RSV vaccines in development. In the ConquerRSV trial, mRNA-1345 (Moderna) vaccine, targeting prefusion F glycoprotein, showed vaccine efficacy of 83.7% against RSV lower respiratory tract disease in older adults.80 At least one has shown the ability to produce robust neutralising antibody and cell-mediated responses,81 and safety data published for another suggests a profile that is comparable to COVID-19 mRNA vaccines in that a majority of the patients have non-serious local or systemic reactogenicity.82 These mRNA vaccines, as well as the two recently approved protein-based vaccines, need to be evaluated in patients with AIIRD and other immunosuppressed populations.

Of note, the novel bivalent RSV prefusion F vaccine has shown a vaccine efficacy of 66.7% (96% CI 28.5% to 85.8%).79 In a recent study, mRNA-based RSV preF exhibited a vaccine efficacy of 83.7% (96% CI 66.0% to 92.2%).83 To further clarify the comparative effectiveness between mRNA and preF protein-based vaccines, a head-to-head trial is warranted.

Cytomegalovirus

Cytomegalovirus (CMV) infection in immunocompromised patients results from reactivation of latent CMV reinfection.88 Approximately 1 in 200 babies are born with CMV infection, and 1 in 5 of them will experience devastating sequelae including hearing loss, seizure and blindness.89 Controlling CMV infection might be crucial, especially in childbearing patients with AIIRD with dysfunctional T-cell immunity such as women with systemic lupus erythematosus (SLE).90–92

For effective immunity against CMV, targeting six distinct proteins, including a glycoprotein B (one mRNA sequence) and the glycoprotein subunits of the pentameric complex (five mRNA sequences) is essential. The ability of mRNA vaccines, allowing the incorporation of six different mRNAs, each encoding a specific protein, has greatly facilitated the development of a vaccine against this pathogen.93 It is a crowning example of ‘plug and play’ aspect of mRNA vaccines. Moderna’s mRNA-1647 has been tested in diverse clinical scenarios including post-haematopoietic stem cell transplantation. Early phase 2 data suggest typical levels of reactogenicity for an mRNA vaccine and a robust antibody response.94

Epstein-Barr virus

Epstein-Barr virus (EBV) establishes a lifelong infection in over 95% of individuals by their 40s. While often asymptomatic in childhood, its clinical implications become more significant later in life, with approximately 1% of patients experiencing serious complications, such as hepatitis and neurological issues.95 EBV has been implicated in the development of various cancers, including Burkitt and Hodgkin’s lymphomas, as well as several autoimmune disorders like RA, SLE and multiple sclerosis.96 97 As such, a prophylactic vaccine holds the potential to reduce the severe EBV infection and potentially the associated risks of malignancies and autoimmune diseases. Multiple vaccine classes, including subunit vaccines, epitope vaccines and DNA vaccines, are currently in development. Moderna’s mRNA-1189, designed to target glycoproteins gp-350, gB, gH/gL and gp42 is currently in phase 1 clinical study.98 99

Pneumococcal vaccines

The risk for invasive infection with Streptococcal pneumoniae is increased in patients with AIIRD. Currently, the 23-valent pneumococcal polysaccharide vaccine, the 13-valent and 20-valent pneumococcal conjugate vaccine are available. To date, there is no mRNA vaccine for pneumococcal pneumonia.

Multivalent and combination vaccines

mRNA technology can encode epitopes from one or more pathogens simultaneously. Moderna’s mRNA-1045 vaccine targets both RSV and influenza, whereas mRNA-1083 targets influenza and COVID-19. Furthermore, mRNA-1230 aims to tackle all three pathogens: influenza, RSV and COVID-19 infection. These vaccines are currently in the early phases of clinical trials. Combining existing and novel vaccines to prevent several common respiratory infections such as influenza, RSV and COVID-19 can postulate the strategy of a ‘pan-respiratory vaccine’. Numerous trials are underway to investigate potential interactions or interference of mRNA vaccines with other vaccines concerning efficacy and safety in clinical settings (table 3). mRNA vaccines as immunosuppressive therapy

The selective inhibition of autoreactive immune cells, as opposed to a broad suppression of the entire immune system, has become increasingly realistic. The transfection of antigen-presenting cells (APCs) with nucleoside-modified, single-strand non-inflammatory mRNA encoding auto-antigens ensures that transfected APCs present auto-antigens with no to low-level expression of co-stimulatory molecules, generating regulatory T cells for peripheral tolerance.100 In experimental autoimmune encephalitis in mice, the introduction of modified N1-methylpresduouridine mRNA, encoding myeline oligodendrocyte glycoprotein, in dendritic cells in lymphoid tissue was effective in mitigating the autoimmune response. The innovative approach to induce a peripheral tolerance holds promise to treat autoimmune diseases characterised by well-defined antigens, such as antiphospholipid syndrome.

Role mRNA vaccines in cancer treatment

By comparing tumour and normal sequences, mRNA encoding tumour-specific or tumour-associated antigens are synthesised and delivered to dendritic cells for presentation to T cells.101 Vaccination with cancer-specific mRNA elicits a robust adaptive immune response with long-term immune memory against cancer antigens, outperforming peptide-based cancer vaccines.102 Combining cancer vaccines with immune checkpoint inhibitors enhances anticancer immunity, showing promising results in the treatment of various cancers, such as lung cancer, melanoma and pancreatic cancer, as evidenced in early-stage clinical trials.103

Conclusions

In summary, mRNA vaccines are reshaping the vaccination landscape, providing new powerful tools not only to combat existing and emerging infectious pathogens but also to potentially treat autoimmune diseases. Even though they are not without safety concerns including reactogenicity, flares of underlying autoimmune diseases and a potential for causing autoimmune disease, the benefit clearly outweighs these potential side effects. Further research is imperative to thoroughly assess the efficacy and safety of new mRNA vaccines in patients with AIIRD.