Since the onset of the COVID-19 pandemic, SARS-CoV-2 vaccine development has progressed
at an unprecedented rate, with recent phase 3 trial data offering the tantalising
prospect of achieving herd immunity.1, 2, 3 Until now, researchers have focused on
the contribution of specific liver disease phenotypes, including transplantation and
immunosuppression, to COVID-19 susceptibility and outcome. However, the hepatology
community must now urgently turn its attention to characterising SARS-CoV-2 vaccine
responses in these vulnerable patient groups.
The Pfizer/BioNTech BNT162b2 mRNA, Moderna mRNA-1273, and the AstraZeneca/University
of Oxford ChAdOx1-nCoV-19 chimpanzee adenovirus (ChAd) vector vaccines have each reported
excellent safety profiles, marked efficacy in preventing symptomatic COVID-19 (62–95%),
and have all gained rapid regulatory approval.1, 2, 3 Currently, it remains unclear
why a significant minority of those vaccinated appear susceptible to SARS-CoV-2, although
both host factors (eg, underlying chronic diseases or genetic susceptibility) and
viral factors (eg, high viral load exposure, specific viral variants) are likely to
have a contributory role.
Despite the inclusion of nearly 100 000 participants in these trials, data for patients
with liver disease are extremely limited (panel
). In the Pfizer vaccination study, 217 (0·6%) of 37 706 participants had liver disease,
and only three (<0·1%) had moderate to severe liver disease. A similarly low proportion
of patients with liver disease were included in the Moderna trial (196 [0·6%] of 30 351).
The ChAdOx1-nCoV-19 vaccine trial explicitly omitted patients with pre-existing liver
pathology. Notably, in each study the criteria used to classify liver disease and
its severity remain unclear. In addition, all trials listed systemic immunosuppression
as an exclusion criterion, thus preventing extrapolation of the data to immunosuppressed
liver transplant recipients or patients with autoimmune liver disease. Furthermore,
granular detail regarding liver safety profiles remains largely unpublished, although
abnormal liver biochemistry was reported in only one of 12 021 participants receiving
ChAdOx1-nCoV-19. ChAd vaccines for hepatitis C virus (HCV) have previously been safely
given to a small number of patients with non-cirrhotic chronic HCV infection.
4
However, a detailed understanding of SARS-CoV-2 vaccine safety and the immunological
response in patients with liver disease will almost exclusively come from post-licensing,
real-world investigation.
Panel
Involvement of patients with liver disease in phase 3 SARS-CoV-2 vaccine trials and
key outstanding questions
Chronic liver disease and cirrhosis
Trial inclusion and exclusion criteria
•
Pfizer/BioNTech: “liver disease” included but not defined
•
Moderna: “liver disease” included but not defined
•
Oxford/AstraZeneca: “liver disease” excluded (except Gilbert syndrome), “alcohol and
drug dependency…injecting drug abuse in the 5 years preceding enrolment” excluded
Key outstanding questions
•
Magnitude and duration of vaccine response
•
Disease severity in predicting vaccine response
•
Differential efficacies of single doses or additional booster doses
•
Risk of liver injury unknown
Liver transplantation
Trial inclusion and exclusion criteria
•
Pfizer/BioNTech: “Individuals who receive treatment with immunosuppressive therapy”
excluded
•
Moderna: “Immunosuppressive or immunodeficient state” or “systemic immunosuppressants
or immune-modifying drugs for >14 days” excluded
•
Oxford/AstraZeneca: “Any confirmed or suspected immunosuppressive or immunodeficient
state” excluded
Key outstanding questions
•
Magnitude and duration of vaccine response
•
Durability of response post-transplantation; optimal timing of prime and boost vaccination
in relation to transplantation
•
Interactions with specific immunosuppression regimens
•
Differential efficacies of single doses or additional booster doses
•
Risk of liver injury unknown
Immunosuppressed autoimmune liver disease (eg, autoimmune hepatitis)
Trial inclusion and exclusion criteria
•
Pfizer/BioNTech: “Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention” excluded
•
Moderna: “Immunosuppressive or immunodeficient state” or “systemic immunosuppressants
or immune-modifying drugs for >14 days” excluded
•
Oxford/AstraZeneca: “Any autoimmune conditions” excluded
Key outstanding questions
•
Magnitude and duration of vaccine response
•
The effects of specific immunosuppression regimens of vaccine response
•
Interactions with specific immunosuppression regimens
•
Differential efficacies of single doses or additional booster doses
•
Risk of liver injury unknown
Patients with advanced liver disease have well recognised deficiencies in innate and
humoral immunity, termed cirrhosis-associated immune dysfunction (CAID). Although
attention has mostly focused on mechanisms leading to severe bacterial infections,
CAID has also been shown to predispose to a variety of viral or fungal related diseases.
5
This same immune dysfunction might partly explain the severe complications of COVID-19
observed in patients with decompensated cirrhosis
6
and contribute to the impaired immunological responses seen with existing vaccinations.
For example, rates of seroconversion after hepatitis B virus (HBV) immunisation, and
the durability of humoral immunity after pneumococcal and influenza vaccination are
all markedly reduced in patients with cirrhosis.7, 8, 9 It is therefore likely that
patients with cirrhosis will have attenuated immune responses to SARS-CoV-2 vaccination.
Nonetheless, given the high COVID-19-related mortality in patients with decompensated
cirrhosis, it remains of utmost importance to prioritise vaccination in this subgroup.
6
Patient education regarding the benefit of SARS-CoV-2 vaccination programmes will
also be essential, particularly given that routine immunisation uptake in patients
with cirrhosis is often suboptimal.
10
The value of routine immunisation in liver transplant recipients is well established,
with vaccine immunogenicity greatest in the pre-transplantation rather than the post-transplantation
setting, even in the context of advanced liver disease. Current guidelines therefore
recommend pre-transplant vaccination where possible, with any subsequent immunisation
deferred until doses of immunosuppression have been reduced to maintenance levels.
11
The optimal timing of SARS-CoV-2 vaccine delivery within the transplantation pathway
is undetermined, but currently due to the high global burden of COVID-19 should most
likely be administered as soon clinically available. Blunting of the response in immunosuppressed
liver transplant recipients is well recognised, with lower antibody titres reported
following influenza, hepatitis A virus, HBV, and pneumococcal vaccinations.
12
At present, the product information for the mRNA vaccines recommends against their
use in those with immunosuppressive conditions or when receiving immunosuppressive
medications. This is presumably related to the lack of specific efficacy and safety
data in these subpopulations. However, neither the ChAdOx1-nCoV-19 or the mRNA vaccine
platforms contain live or attenuated virus and it therefore seems unlikely that immunisation
represents a particular safety concern for these patients. Although historically there
have been anxieties that vaccination in transplant recipients may lead to the development
of alloimmunity and graft rejection, no clinical evidence has emerged to support this.
12
Although liver transplant recipients have comparable rates of COVID-19-related mortality
to the matched general population,
13
they do have higher rates of admission to intensive care and may have been relatively
more protected throughout the pandemic due to enhanced social distancing or shielding.
Therefore, we still believe this group remains a vulnerable population and should
be prioritised for vaccination, with the likely benefits far outweighing the potential
risks. However, until it is established whether patients with liver disease and transplantation
achieve optimal protection after immunisation, clinicians should remain vigilant for
post-vaccination COVID-19 in these cohorts.
More work is needed to define the precise laboratory correlates of vaccine protection
following delivery of the mRNA and ChAdOx1-nCoV-19 platforms. Both vaccine types induce
high concentrations of anti-spike IgG antibodies as measured ex-vivo14, 15 and also
generate high levels of spike-specific CD4+ and CD8+ T cells,14, 15 which might improve
durability of B-cell responses and help protect against future infection. In evaluating
patient responsiveness it is therefore vital to assess for the magnitude and durability
of both humoral and cellular responses.
Finally, despite the frequency of post-vaccination SARS-CoV-2 infection in liver disease
cohorts being unknown, it is likely to be rare in absolute terms. Therefore, large
scale case reporting through platforms such as the COVID-Hep and SECURE-Cirrhosis
registries may be the only mechanism through which to draw meaningful conclusions.
Furthermore, disentangling the relative contributions of vaccine type, liver disease
phenotype, and host factors to the immunisation response will require wide collaborative
efforts to pool clinical and laboratory data. Currently, advice regarding vaccine
delivery in disease subpopulations is inconsistent and subject to geographical variation.
Detailed investigation of immune responses is therefore vital to ultimately allow
the standardisation of vaccination guidelines. As we usher in the new era of SARS-CoV-2
immunisation, it is now of fundamental importance to examine the effect of new vaccines
on patients with liver disease, for whom evidence is thin yet clinical consequences
profound.