Safety concerns have arisen again for healthcare workers who have been shielding during the covid-19 pandemic. Shielding guidance for clinically extremely vulnerable (CEV) individuals in England will pause tomorrow (31 March 2021). The expectation that CEV healthcare workers will confidently return to patient facing roles once vaccinated poses urgent questions about covid-19 vaccine efficacy for the immunosuppressed. CEVs are an extremely heterogeneous group, many of whom have cancer or are taking a variety of immunosuppressant agents. Vaccine immunogenicity has not yet been adequately explored in this population, leaving thousands of healthcare workers potentially at risk from serious covid-19 infection, despite having been vaccinated.
Humoral responses to SARS-CoV-2 are mediated by the production of antibodies which bind to viral surface glycoproteins, mainly the spike and the nucleocapsid proteins. Although the immunological mechanisms of covid-19 disease presentation and severity are manifold, the majority of clinical trials regard semi-quantitative anti-spike antibody (sAb) titres as useful biomarkers, predicting successful protective immune responses after SARS-CoV-2 exposure both via covid-19 infection and also from vaccination.  Lower sAb titres are associated with more severe covid infection, and also with risk of repeat infection, especially in older cohorts. [2,3] Covid-19 vaccines currently used in the UK lead the immune system to produce antibodies against the spike protein only, however sAb assays are not yet available on the NHS.
Recently the preliminary results of the SOAP study from King’s and the Francis Crick Institute were reported. The anti-SARS-CoV-2 antibody responses at week three following the first dose of the vaccine were only 39% in the solid and 13% in the haematological cancers, compared to 97% in those without cancer. The authors of the study believe there should be urgent re-evaluation of UK policy for the BNT162b2 (Pfizer-BioNtech) dosing interval for all cancer patients, and likewise for other high-risk groups of immunosuppressed patients. 
Another study showed the majority of organ transplant recipients did not mount appreciable sAb responses after a single dose of SARS-CoV-2 mRNA vaccine, with reduced response in those receiving anti-metabolite immunosuppression.  This suggests that such patients will remain at higher risk for covid-19 despite their first vaccination dose, yet will still need to wait 12 weeks for their second dose.
The OCTAVE study recently started looking at vaccine responsiveness in the immunocompromised. However, at present there are scant data examining the impact of immunosuppressant medications on covid vaccine effectiveness. There is some evidence that the use of immunosuppressants is associated with higher mortality rates in covid infection. [6,7] The protective effect of shielding may have concealed the full extent of covid-19 infection risk in the immunosuppressed.
Many patients on immunosuppressant therapy take multiple agents in combination, which makes the assessment of risk relating to a specific agent even more challenging. There has been discussion within specialist medical groups about the possible merits of withholding immunosuppressants in stable patients around the time of vaccines to encourage an enhanced antibody response, however, there are as yet no published studies in this area to support this practice. Altering dosing schedules is an individual decision to be made by the clinician and their patient, as there is the risk of inducing a troublesome disease flare. We hope that by highlighting our concerns, we will raise awareness of the need to test vaccine response in immunosuppressed individuals, rather than just assuming that vaccination will automatically provide the expected “immunity” protection after two doses. We agree with the authors of the SOAP study that “one size does not fit all,” and believe there needs to be an agreed NHS pathway ensuring routine testing for sAb vaccine response for this group.  Testing will increase safety and will more accurately inform the conversation around risk for immunosuppressed HCWs. With shielding for CEV due to end imminently, there needs to be urgent consideration of how to manage those who are immunosuppressed.
NHS England replied to a letter of concern from the Presidents of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland recommending that where staff have had poor response to vaccination, staff and employers should undertake a shared decision risk assessment for deployment, including the option for working remotely at home for some. [9,10] However, currently there is no sAb testing pathway for vaccination response to facilitate such discussions.
We would be delighted if investigators could widen their study protocols to specifically examine immunogenicity among those on different immunosuppressive agents. Meanwhile, it may be helpful to develop expert consensus guidance (as per the American Society of Rheumatology with respect to both vaccine intervals and optimal timing of immunosuppressant medication in the peri-vaccination period.  We also await developments in the possible provision of booster vaccines to better protect those with lower immunity from variants, especially in the light of possible links between partially immune immunocompromised individuals and new VOC development. 
Sarah Todd, Retainer GP, North Derbyshire. @SarahJTodd
Hilary Swales, Consultant Anaesthetist, Southampton. @HilarySwales
Emma Casely, Specialist Registrar in Anaesthetics, London.
Kerry Bramley, Foundation Year 2 Doctor, East Midlands.
Competing interests: none declared