IMMUNIZATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: WHAT WE KNOW TO DATE
Patients with inflammatory bowel disease (IBD) may be at increased risk of developing
certain vaccine-preventable infections such as influenza and pneumococcal pneumonia.
The effectiveness and safety of vaccinations may be altered in patients with IBD due
to the underlying immune dysregulation inherent to IBD and/or the immunosuppressive
therapy that is prescribed for the disease.
The Canadian Association of Gastroenterology (CAG) recently completed a comprehensive
and rigorous systematic review and grading of evidence of immunization with inactivated
and live vaccines in patients with IBD for a clinical practice guideline.(1, 2) The
evidence to date suggests that patients with IBD on immunosuppressive therapy may
have a lower immune response to certain vaccines. However, inactivated (or non-live)
vaccines are safe with no serious adverse events (SAEs) in patients with IBD regardless
of whether or not they are on immunosuppressive therapy. The use of live vaccines
in patients with immune-mediated diseases (including patients with IBD) on immunosuppressive
therapy is also generally safe, although rare SAEs have been reported (3). Both the
US Centers for Disease Control and Prevention (CDC) and the Canadian National Advisory
Committee on Immunization (NACI) recommend against live vaccines ‘in patients on immunosuppressive
therapy equivalent to ≥ 20 mg or 2 mg/kg/day of prednisone for ≥ 14 days’ (4,5).
RISKS OF CONTRACTING SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-CoV-2)
INFECTION OR DEVELOPING SEVERE COVID-19 (CORONAVIRUS DISEASE 2019) OUTCOMES IN PATIENTS
WITH IBD: WHAT WE KNOW TO DATE
It is unknown whether patients with IBD have a different baseline risk of contracting
SARS-CoV-2 infection than people without IBD with similar levels of viral exposure,
but it is unlikely that the risk is any lower. The evidence to date suggests that
patients with IBD who have COVID 19 (including those on long-term biologics or nonsteroid
immunomodulatory therapies) may not have an increased risk of severe outcomes (hospitalization
or death) compared to COVID-19 patients without IBD (6). However, recent corticosteroid
use may be associated with a higher risk of severe COVID-19 outcomes (6,7). The risk
factors for severe COVID-19 outcomes in patients with IBD appear to be similar to
those widely recognized in COVID-19 patients without IBD. These risk factors include
advanced age and multiple comorbidities (6,7).
SAFETY AND EFFECTIVENESS OF MESSENGER RNA (mRNA) COVID-19 VACCINES: WHAT WE KNOW TO
DATE
Pfizer-BioNTech COVID-19 vaccine (BNT162b2) is a lipid nanoparticle-formulated nucleoside-modified
mRNA vaccine that encodes a modified form of the spike protein of SARS-CoV-2. The
CDC has systematically evaluated the certainty of evidence for the benefits and harms
of Pfizer-BioNTech COVID-19 vaccine from one Phase I randomized controlled trial (8)
and one Phase II/III randomized controlled trial (9) using the GRADE approach to inform
its recommendations (10,11). A lower risk of symptomatic COVID-19 was observed with
vaccination compared to placebo (relative risk [RR] 0.05; 95% confidence interval
[CI] 0.02 to 0.10, and absolute risk [AR] 9 fewer per 1000; 95% CI from 9 fewer to
8 fewer). This corresponds to a vaccine efficacy of 95.0% (95% credible interval,
90.3% to 97.6%). The certainty of evidence for symptomatic COVID-19 was rated as high,
although there were some concerns for indirectness due to the short duration of follow-up
(2 months) (Indirectness: Direct evidence comes from research that directly compares
the interventions in which we are interested when applied to the populations in which
we are interested and measures the outcomes important to patients. As per the GRADE
approach, we can have concerns about indirectness when the population, intervention,
outcomes, or comparisons differ from those in which we are interested.). The vaccine
was also associated with numerically fewer hospitalizations due to COVID-19 (RR 0.0;
95% CI 0.0 to 1.10) and all-cause deaths (RR 0.50, 95% CI 0.09 to 2.73). The certainty
of evidence regarding hospitalization due to COVID-19 and death was downgraded to
low and very low respectively due to indirectness and imprecision. In terms of harms,
the incidence of SAEs was low and was comparable between the vaccine and placebo arms
(incidence rate 0.6% versus 0.5%; RR 1.14; 95% CI 0.89 to 1.47). The certainty of
evidence for harms was downgraded to moderate due to indirectness related to the short
duration of follow-up and imprecision related to the large sample size generally needed
to confidently assess the incidence of rare SAEs. From available data, the vaccine’s
efficacy was consistent across genders, age groups, ethnic and racial groups, and
people with pre-existing medical conditions. Overall, the efficacy and safety data
support a positive balance between benefits and harms for Pfizer-BioNTech COVID-19
vaccine.
The CDC has also systematically evaluated the certainty of evidence for benefits and
harms of Moderna COVID-19 vaccine using the GRADE approach (12,13). Data were reviewed
from one Phase II randomized controlled trial and one Phase III randomized controlled
trial provided to the CDC by the sponsor and the FDA. Similar to Pfizer-BioNTech COVID-19
vaccine, the certainty of evidence for prevention of symptomatic COVID-19 was rated
as high (RR 0.06; 95% CI 0.03 to 0.11 and AR 13 fewer per 1000; 95% CI from 13 fewer
to 12 fewer) for Moderna COVID-19 vaccine. The certainty of evidence for harms in
terms of SAEs was rated as moderate (incidence rate 1.0% versus 1.0%; RR 0.96; 95%
CI 0.77 to 1.20). Overall, the efficacy and safety data also support a positive balance
between benefits and harms for Moderna COVID-19 vaccine.
It is important to note that specific high-risk or vulnerable populations such as
young children, very elderly persons (>85 years of age), pregnant or lactating women,
and those who are immunocompromised (either due to immunosuppressive therapy or an
immunocompromising condition) were excluded from these randomized clinical trials.
Several long-term pharmacoepidemiology studies are to be conducted to assess for rare
SAEs in diverse populations including these important subgroups not yet studied.
CAG ENDORSES THE CDC RECOMMENDATIONS FOR MRNA COVID-19 VACCINES
On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for Pfizer-BioNTech COVID-19 vaccine in persons aged 16 years
and older for prevention of COVID-19. This was immediately followed by an interim
recommendation for the use of this vaccine by the CDC’s Advisory Committee on Immunization
Practices (ACIP). On December 18, 2020, the FDA issued an EUA for Moderna COVID-19
vaccine in persons aged 18 years and older. This was also followed by an interim recommendation
for the use of this vaccine by the CDC’s ACIP.
The CDC (14) also issued guidance for vaccination of special populations including
persons with underlying medical conditions and immunocompromised persons:
Persons With Underlying Medical Conditions
“COVID-19 vaccine may be administered to persons with underlying medical conditions
who have no contraindications to vaccination. Phase 2/3 clinical trials demonstrated
similar safety and efficacy profiles in persons with some underlying medical conditions,
including those that place them at increased risk for severe COVID-19, compared to
persons without comorbidities”.
Immunocompromised Persons
“Persons with HIV infection, other immunocompromising conditions, or who take immunosuppressive
medications or therapies might be at increased risk for severe COVID-19. Data are
not currently available to establish vaccine safety and efficacy in these groups.
Persons with stable HIV infection were included in phase 2/3 clinical trials, though
data specific to this group are not yet available. Immunocompromised individuals may
still receive COVID-19 vaccination if they have no contraindications to vaccination.
However, they should be counseled about the unknown vaccine safety profile and effectiveness
in immunocompromised populations, as well as the potential for reduced immune responses
and the need to continue to follow all current guidance to protect themselves against
COVID-19”.
On the other hand, NACI in Canada has advised that “COVID-19 vaccine should not be
offered to the following populations excluded from clinical trials until further evidence
is available. However, if a risk assessment deems that the benefits of vaccine outweigh
the potential risks for the individual (e.g., where the risk of severe outcomes of
COVID-19 and risk of exposure to SARS-CoV-2 is high) or for the fetus/infant (in the
case of pregnancy/breastfeeding) and if informed consent includes discussion about
the insufficient evidence in this population, then a complete series of authorized
COVID-19 vaccine may be offered to individuals in the following populations: immunosuppressed
due to disease or treatment, individuals with an autoimmune condition, pregnant or
breastfeeding, and adolescents 12 to 15 years of age (only Pfizer-BioNTech COVID 19
vaccine may be offered)” (15)
The CAG endorses the CDC recommendations for the use of mRNA COVID-19 vaccines in
special populations, after assessing the evidence using the GRADE approach. Specifically,
in patients with IBD not on immunosuppressive therapy, we recommend the COVID-19 vaccine
be given (strong recommendation, moderate certainty of evidence). In patients with
IBD on immunosuppressive therapy, we suggest the COVID-19 vaccine be given (conditional
recommendation, low certainty of evidence).
As per the GRADE approach, a strong recommendation means that we are confident that
the benefits of following the recommendation clearly outweigh the harms, so the course
of action should apply to most patients. A conditional recommendation means that the
desirable effects of adherence to a recommendation probably outweigh the undesirable
effects, but we are not confident about these tradeoffs due to low or very low certainty
of evidence, uncertainty regarding the balance of benefits and harms, uncertainty
in patients’ values and preferences or questionable cost-effectiveness. Thus, conditional
recommendations require shared decision-making as different choices will be appropriate
for different patients. Patients with IBD are not considered immunosuppressed at diagnosis,
but subsequently may become immunosuppressed due to IBD therapies. It is important
to note that there is no standard definition of immunosuppression. The degree to which
immunosuppressive therapy causes clinically relevant immunosuppression is dose related
and varies by medication. The medications and doses used in patients with IBD would
generally cause less severe immunosuppression compared to patients with active HIV
infection or post-transplant treatment.
The certainty of evidence for CAG’s recommendations was based on the CDC’s assessments
of the evidence for the general population. In patients with IBD not on immunosuppressive
therapy, the certainty of evidence for benefits or harms was not further downgraded
compared to the assessment for the general population. Given the high certainty of
evidence for benefits and moderate certainty of evidence for lack of harms in patients
with IBD not on immunosuppressive therapy, the overall certainty of evidence for CAG’s
recommendation for this population is moderate.
However, in patients with IBD on immunosuppressive therapy, the certainty of evidence
for both benefits and lack of harms was further downgraded to low due to indirectness
of the population. Therefore, the overall certainty of evidence for CAG recommendation
for this population is low.
The mRNA technology used in Pfizer-BioNTech and Moderna COVID-19 vaccines has been
studied for more than a decade. mRNA vaccines do not contain a live virus and do not
carry a risk of causing the viral disease in the vaccinated person. Based on cumulative
evidence of vaccinations in patients with IBD, it is biologically implausible for
mRNA vaccines to cause catastrophic harms in patients with IBD on or not on immunosuppressive
therapy, while other serious harms in these patients are highly unlikely. Based on
the evidence of other non-live vaccines administered to IBD patients on immunosuppressive
therapy, the efficacy of the COVID-19 vaccine may be similar or slightly reduced,
when compared to persons without IBD or patients with IBD not on immunosuppressive
therapy, but it is extremely unlikely that the vaccine would be entirely ineffective.
The ongoing SARS-CoV-2 pandemic is having significant impact on public health, and
there is no broadly effective treatment currently available. Stopping and/or slowing
the pandemic will require a substantial proportion of the population to acquire immunity
in order to break the chain of transmission. Hence, a safe and effective vaccine can
have a significant impact on the trajectory of the pandemic at this critical time.
During a serious pandemic, it is important that we do not deny susceptible subpopulations
a vaccine with proven efficacy and safety in the general population, merely because
these subpopulations were not studied in the initial clinical trials. Such exclusions
from the vaccination program risk harming not only the excluded subpopulations, but
also the general population by compromising or delaying the potential for herd immunity.
Specifically, for patients with IBD, the GRADE approach allows incorporation of indirect
evidence from decades of research on vaccines, and justifies inclusion of these patients
in a vaccination program. If new evidence emerges that necessitates revising these
recommendations, the CAG will provide timely guidance via its website and its official
journal, the Journal of the Canadian Association of Gastroenterology.
CANADIAN ASSOCIATION OF GASTROENTEROLOGY COMMUNIQUÉ
This communiqué on COVID-19 vaccination in patients with inflammatory bowel disease
was developed under the direction of Drs. Frances Tse (CAG Chair Practice Affairs)
and Grigorios Leontiadis (CAG VP Clinical Affairs), in accordance with the policies
and procedures of the Canadian Association of Gastroenterology (CAG) and under the
direction of CAG Clinical Affairs. The communiqué was developed following a thorough
consideration of medical literature and the best available evidence and clinical experience.
The communiqué aims to provide a reasonable and practical approach to care for specialists
and allied health professionals charged with the duty of providing optimal care to
patients and families, and can be subject to change as scientific knowledge and technology
advance and as practice patterns evolve. The communiqué is not intended to be a substitute
for physicians using their individual judgment in managing clinical care in consultation
with the patient, with appropriate regard to all the individual circumstances of the
patient, diagnostic and treatment options available, and available resources.