Review Article

Vaccination for Patients With Inflammatory Bowel Disease During the COVID-19 Pandemic

Jayne Doherty; Sean Fennessy; Roisin Stack; Neil O' Morain; Garret Cullen; Elizabeth J. Ryan; Cillian De Gascun; Glen A. Doherty

Disclosures

Aliment Pharmacol Ther. 2021;54(9):1110-1123. 

In This Article

Novel Vaccines Against COVID-19

Vaccines against SARS-CoV-2 that elicit protective immune responses are crucial for the prevention and mitigation of the morbidity and mortality associated with severe COVID-19. Various strategies have been employed to rapidly develop vaccines including standard inactivated virus vaccines, live attenuated vaccines, and newer technologies such as nucleic acid vaccines and viral-vectored vaccines. To date, multiple vaccines against COVID-19 have entered pre-clinical and clinical trials.[61] The four lead vaccines to date available are two viral-vector and two mRNA-based vaccines. Here we will provide a short summary of each vaccine focusing on results from current trials and briefly discuss the current data on response rates in patients with IBD to the COVID-19 vaccines and the gaps in knowledge regarding patients with IBD and vaccination.

Viral Vector-based Vaccines

Viral-vectored vaccines rely on the delivery of one or more antigens encoded in the context of an unrelated modified virus. Prior to the COVID-19 pandemic only one viral-vectored vaccine called Dengvaxia (Sanofi-Pasteur), a recombinant Dengue vaccine has been licensed for human use.[62]

Given the large amount of different viral vectors available and the vast knowledge gathered about their manipulation and function as immunogens, viral vector-based vaccines represent a highly versatile platform for vaccine development. The viral vectors themselves are detected as foreign as they trigger PRRs and initiate innate immune responses, thus mimicking natural viral infection inducing potent immune responses. Strong antigen-specific cellular and humoral immune responses against the target antigen can be induced by these vaccines (Figure 1). One study looking at the Canarypox-virus vaccine vector ALVAC found this viral-vector acts as an adjuvant through a mechanism requiring natural killer cells derived IFN-γ, DC activation and chemokine secretion.[63] We have recently demonstrated that NK cells isolated from the blood of IBD patients produce markedly reduced levels of IFNγ and this suboptimal NK cell response may impact on the ability of patients with IBD to respond to this class of vaccine.[64]

Two viral vector-based vaccines against COVID-19 have been approved to date.

AstraZeneca has developed a chimpanzee adenovirus-vectored vaccine that encodes the spike glycoprotein of SARS-CoV-2 (ChAdOx1 nCoV-19 vaccine).[65] Phase 1/2 trial showed the induction of humoral responses after the first dose of the vaccine and an additional increase in humoral immune outcomes after the second dose.[66] Subsequently a large, randomised placebo control phase 3 trial of the ChAdOx1 nCoV-19 vaccine involving 23,848 adults reported this vaccine is highly effective in preventing COVID-19. No hospitalisations or severe cases of COVID-19 were reported in participants receiving the vaccine. There was a total of 131 COVID-19 cases reported, 30 (0.5%) in the vaccinated group and 101 (1.7%) in the control group.[67] In this study overall vaccine efficacy was 70% which was statistically significant compared to placebo. No serious safety events related to the vaccine were reported.[67] The vaccine generated similarly robust immune responses against the SARS-CoV-2 virus across all age groups.[67] The UK Medicines and Healthcare products Regulatory Agency (MHRA) and EMA have provided authorisation for emergency supply of the ChAdOx1 nCoV-19 vaccine.[68,69]

Since the approval of the AstraZeneca vaccine, both EU and UK regulators have investigated reports of unusual blood clots after receiving the ChAdOx1 nCoV-19 vaccine. The EMA's investigating committee reviewed 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis reported in the EU's drug safety database as of March 2021, 18 of which were fatal. At that point, around 25 million people in the EU and UK had received the AstraZeneca vaccine. The agency said that most cases occurred in women aged under 60 within two weeks of vaccination.[70,71] Overall, it was found 1 in 250 000 people with the AstraZeneca vaccine will develop blood clots with low platelets. However, the risk of developing a clot from COVID-19 infection is much higher with a prevalence of 7.8% in one study for pulmonary embolism and 1.6% for a stroke.[72] The MHRA have advised offering an alternative vaccine where possible to those under 30 years of age given risk-benefit calculation.[71] Both the EMA and the UK's MHRA have advised that unusual blood clots with low blood platelets should be listed as a very rare side effect of the AstraZeneca vaccine but overall, the vaccine is very safe and effective.[70,71]

The Janssen Pharmaceutical Companies of Johnson & Johnson have developed a viral vector-based vaccine, the Ad26.COV2-S vaccine, after preclinical studies demonstrated a single dose provides protection against SARS-CoV-2 infection in rhesus macaques.[73] Results from phase 1/2 trials found a single dose of this adenovirus serotype 26-vectored vaccine induced strong neutralising antibody responses.[74] Given these promising results a randomised, double-blind, placebo-controlled, phase 3 trial called the ENSEMBLE trial of the replication-defective Ad26.COV2-S vaccine was initiated. 43 783 participants were recruited with 468 symptomatic cases of COVID-19 identified during the study. Results reported Janssen's Ad26.COV2-S vaccine was 66% effective in preventing moderate-to-severe COVID-19, 28 days after vaccination.[75] The level of protection against moderate-to-severe COVID-19 infection was 72% in the United States, 66% in Latin America and 57% in South Africa.[75] The ENSEMBLE trial was the first to include efficacy against the newly emerging strains of coronavirus. The Ad26.COV2-S vaccine was 85% effective in preventing severe disease across all regions studied. 41% of participants had comorbidities associated with an increased risk for progression to severe COVID-19.[75] Efficacy against severe disease appeared to increase over time with no reported COVID-19 cases in vaccinated participants reported after day 49.[75] Overall, this vaccine was well tolerated. EUA of this vaccine has been approved by the EMA.[76] As seen with the AstraZeneca vaccine blood clots have been reported post-vaccination with this vaccine. The EMA's safety committee advised a warning about unusual blood clots with low blood platelets should be added to the product information for the Janssen COVID-19 vaccine. Of seven cases, blood clots occurred mostly at unusual sites such cerebral venous sinus thrombosis or splanchnic vein thrombosis as seen with the AstraZeneca vaccine.[77]

A third viral vector-based vaccine called the Sputnik V vaccine is currently in phase 3 clinical trials. This vaccine is a human adenoviral vector-based vaccine using a heterologous recombinant adenovirus approach using adenovirus 26 (Ad26) and adenovirus 5 (Ad5) as vectors. The use of two varying serotypes is intended to overcome any pre-existing adenovirus immunity in the population. The second interim analysis (n = 21 977) for this trial of the Sputnik V vaccine reported an efficacy of 95% 21 days after the second dose.[78] So far, 78 confirmed cases of COVID-19 have been identified with 62 cases in the placebo group and 12 in the vaccine group. Although EMA approval is still pending, the Sputnik V vaccine received approval from the Russian Ministry of Health in August 2020 and under emergency rules has been approved for use to vaccinate the population of Russia.

mRNA-based Vaccines

An alternative novel technology deployed for rapid COVID-19 vaccine development involves nucleic acid vaccines. Nucleic acid-based vaccine technologies employ either antigen encoding plasmid DNA or RNA, as messenger RNA or viral replicons. mRNA vaccines can induce both humoral and cellular immune responses, encode any antigen of choice and allow a high degree of adaptability. A major advantage of mRNA vaccines is they offer a flexible one-for-all large-scale, rapid and cost-effective manufacturing process. A variety of preclinical studies have demonstrated the ability of non-replicating mRNA vaccines to induce immune responses and confer protection against pathogens with pandemic potential, such as Zika virus, Ebola virus and influenza.[79–81]

The first mRNA vaccine to receive approval by both the EMA and FDA for EUA was the mRNA-based COVID-19 vaccine launched by Pfizer and BioNTech, BNT162b2. Early results from phase 1/2 trials found that these lipid nanoparticle-formulated, nucleoside-modified mRNA vaccines, elicited receptor-binding domain-specific neutralising IgG and antibodies.[82] Of two vaccine candidates, the BNT162b2 vaccine produced a higher T-cell response and progressed to phase 3 clinical trials.[82] A total of 43 448 participants were recruited for this trial. 21 720 received BNT162b2 vaccine and 21 728 received placebo. Results demonstrated the BNT162b2 vaccine was 95% effective against COVID-19 28 days after vaccination. In subgroup analysis, the observed efficacy of the vaccine in adults over 65 years was over 94%.[83] In this trial, 172 confirmed cases of COVID-19 were observed in the placebo group vs 9 in the vaccine group.[83] No serious safety concerns were reported. The most commonly reported systemic events were fatigue and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.[83] Although there were no reports of anaphylaxis in the clinical trial since approval severe allergy-like reactions have been reported in at least 21 people who received the BNT162b2 vaccine.[84] It is thought this anaphylaxis may be due to polyethylene glycol that has been included in vaccine formulation as a stabiliser.[84] The FDA has advised individuals with severe allergic reactions to vaccines or ingredients in the vaccine should avoid this vaccine.[85] The UK MHRA advised individuals with a history of anaphylaxis to medicine or food not to receive the vaccine.[86]

A second mRNA vaccine, the Moderna vaccine, completed a phase three trial called the COVE trial after promising results from phase 1/2 clinical trials.[87] Positive results from the phase 3 trial showed a vaccine efficacy against COVID-19 of 94% and vaccine efficacy against severe COVID-19 was 100%.[88] In this study, 7000 participants were over the age of 65 and over 5000 participants under the age of 65 had high-risk chronic diseases. In total 42% of participants were defined as a medically high-risk group.[88] One hundred and ninety-six cases of COVID-19 occurred, of which 30 cases were severe. All 30 cases occurred in the placebo group and none in the vaccinated group.[88] No serious safety concerns have been identified to date. The most common adverse reactions reported include injection site pain, fatigue, myalgia, arthralgia, headache, and erythema at the injection site.[88] EUA of this vaccine by the EMA has been granted.

In addition to these leading vaccines, numerous other potential COVID-19 vaccines are in phase 3 clinical trial at present.[89] A summary of potential vaccines is summarised in Table 3 and we will hopefully see results for several other vaccines on the horizon using numerous different mechanisms of action in the next 12 months.

These up-and-coming vaccines have brought about hope and relief worldwide that there is a possible end in sight to the current pandemic however numerous questions remain unanswered. One key unanswered question is how long the vaccine's effectiveness will last which can only be answered with longitudinal observational studies. Vaccine effect can wane over time because of declining immunologic memory or changing antigenicity of the pathogen. A vaccination can be followed with booster doses to maintain a protective level of immunity among susceptible individuals, but the nature of the protection over time must be understood so that an effective vaccination and boosting schedule can be determined.

One possible option to improve immunogenicity to COVID-19 especially in immunocompromised cohorts such as patients with IBD is mixing vaccines.

The main bottleneck in developing vaccines for intracellular infections is the ability to induce strong and long-lasting cell-mediated immunity. Stimulation of a functional CD8 response is often crucial in addition to a Th1-type CD4 T cell response. Over the past decade, studies have shown that prime–boost immunisations can be given with unmatched vaccine delivery methods while using the same antigen, in a "heterologous" prime–boost format. In many cases, heterologous prime–boost can be more immunogenic than homologous prime–boost.[90,91] One study in humans looking at heterologous prime–boost immunisation schedules showed promising results. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine encoding thrombospondin-related adhesion protein partially protected healthy malaria-naive adults against Plasmodium falciparum sporozoite.[92] In a separate study conducted in calves, DNA prime with Ag85B, MPT64 and MPT83 antigens followed by a BCG boost was able to elicit higher immune responses and better protection than BCG alone against Mycobacterium bovis.[93] A heterologous onetime DNA prime and one-time inactivated influenza vaccine boost was also found to be more immunogenic than twice administered homologous prime–boost using either DNA or inactivated influenza vaccine alone.[94] The use of heterologous prime–boost vaccination schedules is currently being looked at for the COVID-19 vaccines and results are promising. In mice models following vaccination with a self-amplifying RNA vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2 investigators found antibody response was higher in two-dose heterologous vaccination regimens than single-dose regimens. Interestingly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice.[95] In one small study in humans 26 individuals received a ChAdOx1 nCoV-19 prime followed by a BNT162b2 boost after an 8-week interval. Antibody titres increased significantly over time resulting in strong neutralisation titres 2 weeks after the BNT162b2 boost. Neutralising activity against the prevalent strain B.1.1.7 was 3.9-fold higher than in individuals receiving homologous BNT162b2 vaccination, only 2-fold reduced for variant of concern B.1.351, and similar for variant B.1.617. No adverse outcomes were noted.[96]

A second key question is how effective are the current vaccines against the numerous new variants of COVID-19 emerging? The COVID-19 vaccines currently approved are expected to provide at least some protection against new virus variants because these vaccines elicit a broad immune response involving a range of antibodies and effector immune cells. Therefore, changes or mutations in the virus should not make vaccines completely ineffective. To date, multiple different variants of the COVID-19 virus have been identified and the four main variants of concern are the alpha, beta, gamma and delta variants. The beta variant was first detected in South Africa and contains the E484K mutation that is thought to help the virus partially evade antibodies. Studies do suggest two doses of COVID-19 vaccination offer strong protection against infection. One study looked at the effectiveness of the Pfizer/BioNTech vaccine to two strains of the beta variant in Qatar. This study found the vaccine was 89.5% effective against the B.1.1.7 variant of COVID-19 and 75% against the B.1.351 variant. Overall vaccine effectiveness against severe COVID-19 for either of these strains was 97%.[97] Janssens viral-vector vaccine was also still in clinical trials when the beta strain emerged and vaccine effectiveness against severe COVID-19 was robust with 82% efficacy at preventing severe disease.[75] Recently the delta variant has become the dominant variant of COVID-19 virus. Reassuringly current vaccines are effective against this strain. After a full course vaccine effectiveness against the delta strain was 88% with the Pfizer/BioNTech vaccine and 67% with the AstraZeneca vaccine.[98] In the event that current vaccines prove to be less effective against one or more variants, it will be possible to change the composition of the vaccines to protect against these variants. WHO has recommended that all countries increase the sequencing of the COVID-19 virus where possible to identify different variants.[99]

For patients with IBD, one of the most pertinent questions is the efficacy of these new vaccines for patients on immunosuppressive medications. To date two studies have looked at response rates to the COVID-19 vaccine in patients with IBD on immunosuppressants. The ICARUS study recently published looked at antibody response to the mRNA COVID-19 vaccines (Pfizer and Moderna) in patients with IBD (n = 48) compared to a control group without IBD (n = 43).[100] There was no significant difference in anti-Spike IgG levels between patients with IBD and the control group at any time points. 85% of patients were receiving biologic therapy at the time of vaccination, all on monotherapy. At the time of this study 33 patients had received one dose of the mRNA vaccine, 15 patients had received both vaccines and 3 patients with IBD had a history of previous COVID-19 infection. All 15 patients with IBD who completed two-dose vaccine schedules seroconverted. Although numbers were small investigators found patients treated with vedolizumab (n = 9) had no significant differences in index values for anti-RBD IgG but had significantly lower anti-S IgG levels compared to patient receiving anti-TNF therapy (n = 5). Reassuringly in this study authors reported a 100% seroconversion rate to complete Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines in IBD patients on biologic monotherapy with robust serological responses.[100] A second larger study from the UK called the CLARITY study compared antibody response rates post one dose of a COVID-19 vaccine. This was a large multicentre study including patients from 92 hospitals.[101] Patients with IBD were vaccinated with either the viral vector AstraZeneca vaccine or the mRNA Pfizer/BioNTech vaccine. Patients included were either receiving vedolizumab (n = 428) or IFX (n = 865) at the time of vaccination. Investigators found mean antibody concentrations were lower in patients treated with IFX than vedolizumab both with the mRNA vaccine and viral-vector vaccine (6.0 U/ml vs 28.8 U/ml).[100] Amongst patients receiving IFX mean antibody concentrations were lower if patients were on concomitant immunomodulators. On multivariate analysis, age over 60 years, immunomodulator use, non-white ethnicity and smoking were independently associated with lower antibody concentrations for either vaccine. Seroconversion rates varied significantly between patients treated with IFX and vedolizumab after one vaccine dose. The lowest rates of seroconversion were observed in participants treated with IFX in combination with an immunomodulator for both the Pfizer (27%) and AstraZeneca (20.2%) vaccines. Highest rates of seroconversion were seen in patients treated with vedolizumab monotherapy.[101] A smaller subset of patients (n = 27) had completed the two-dose vaccination schedule with seroconversion rates of 86% for those on IFX and 86% for those on vedolizumab. In both IFX and vedolizumab treated patient's antibody levels and seroconversion rates were higher after two doses than after one primary vaccine. Seroconversion rates were also higher in patients with IBD who received one vaccination but had a previous history of COVID-19 infection. 82% of patients with previous COVID-19 infection treated with IFX seroconverted and 97% treated with vedolizumab seroconverted after one vaccine dose.[101] Overall to date the CLARITY study is the largest study looking at antibody response to the COVID-19 vaccine in patients with IBD. This study showed anti-SARS-CoV-2 spike antibody levels and rates of seroconversion are lower following vaccination with a single-dose of either COVID-19 vaccine in patients with IBD treated with IFX compared with vedolizumab. Combination therapy with an immunomodulator further reduced immunogenicity to both vaccines in IFX-treated patients. From both the CLARITY and ICARUS studies we can see overall either by vaccination after infection or a second dose of vaccine with either the mRNA or viral vector COVID-19 vaccines rates of seroconversion are high in patients with IBD.[100,101] Both the mRNA and viral vector vaccines appear to induce similar rates of immunity with neither appearing to be more effective than the other in patients with IBD on immunosuppressants.[101] Delayed second dosing of the COVID-19 vaccine should be avoided in patients treated with IFX.[101] A separate study by Ehmsen et al investigated the impact of cancer on antibody response to the COVID-19 vaccines and found antibody titres rapidly decreased from 36 days to 3-month for most patients with cancer, resulting in seroconversion of approximately 10% of the seropositive to seronegative, most prominently for patients with haematologic cancer.[102] For patients with haematologic cancer, seronegativity was significantly associated with certain diagnoses, remission statuses, and treatments, but the lack of T cell responses was only significantly associated with steroid use.[102] Further research is required to confirm the results of the above studies in patients with IBD and better understand whether alterations in the innate immune response in patients with IBD impact vaccine response or whether the impact of different medications such as different biologic therapies or immunomodulators impacts the adaptive immune response and vaccine efficacy. Once the impact of IBD itself, different disease-related factors and medications are determined on vaccine response, observational studies will help determine if manipulation of the timing of biologic therapies in relation to vaccination or use of booster vaccines or heterologous prime–boost vaccination schedules could improve antibody response in sub-cohorts of patients with IBD.

Overall, to date we can be guided by advice provided by the International Organisation for the Study of Inflammatory Bowel Disease and the COVID-19 ECCO taskforce both of which advise patients with IBD should be vaccinated against SARS-CoV-2 at the earliest opportunity possible and vaccination should not be deferred because a patient with IBD is receiving immune-modifying therapies.[103–105] Although data are minimal, the ECCO Taskforce cautiously recommends to use the mRNA vaccine to vaccinate IBD patients on immunomodulatory medication since the vaccine's efficacy to protect against the mild and severe disease was shown to be higher for mRNA vaccines (94%-95%) compared to the viral vector-vaccines, where the mild disease still occurs in about 30%-40% of the vaccinated persons.[104]

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