Some individuals who are immunosuppressed due to underlying health conditions or medical treatment may not mount a full immune response to COVID-19 vaccination. Most of the currently available data comes from immunogenicity studies that have measured binding or neutralising antibody levels. Some studies have also measured cellular responses. Interpretation of both types of evidence is hampered by the lack of agreed correlates of protection. It is further recognised that the correlates of protection against infection, symptomatic disease and severe COVID-19 (hospitalisation and deaths) may differ both in the short and longer term. Comparison across studies is affected by the use of different assays with different test characteristics. Some studies indicate that the profile of antibody responses do not necessarily match those of cellular responses. Most of the data relates to the Pfizer-BNT162b2 vaccine. Preliminary results from UK studies of real-world vaccine effectiveness (VE) in persons who are immunosuppressed suggest only a modest reduction in VE against symptomatic COVID-19, but confidence intervals are wide and overlap with VE estimates for persons who are not immunosuppressed.[footnote 1] Furthermore, as immunosuppression is a heterologous condition that varies widely in severity and in duration, any potential reductions in protection in specific subgroups of the immunosuppressed would be missed by the use of a broader grouping. Clinical effectiveness studies examining more homogeneous sub-groups of persons with specific types of immunosuppression are ongoing. These studies are difficult to conduct due to the relatively small numbers of persons within each sub-group. A few published studies describing the effect of a third dose of mRNA vaccine in persons who are immunosuppressed report increased immune responses in varying proportions of persons. [footnote 2] [footnote 3] [footnote 4] The OCTAVE-DUO trial is a phase 3 multicentre trial randomising patients in the UK to a third dose of Pfizer-BNT162b2 or Moderna mRNA-1273 with immunogenicity outcomes. The trial is expected to report early results in mid to late September and will probably not have sufficient granularity to inform the management of all types of immunosuppression. mRNA vaccines are being used based on consistent evidence of higher antibody levels, even though some studies suggest that cellular responses with AstraZeneca Vaxzevria vaccine are as good or better than after mRNA vaccines.[footnote 5] Emerging evidence suggests that both antibody and cellular immune responses to the primary course are enhanced with heterologous schedules, and therefore a third primary dose with a different vaccine format may be beneficial.[footnote 6] Based on experience with other vaccines, it is expected that some persons who are immunosuppressed may not generate a good immune response regardless of the number of vaccine doses administrated. However, data is not currently available to reliably identify who might, or might not, benefit from a third primary dose of a COVID-19 vaccine. A few studies have suggested that timing of vaccine administration in relation to the underlying disease process or therapy is important in determining the level of immune response. For example, responses were higher in those who had completed treatment for clinically aggressive lymphomas more than 6 months earlier compared to those who had had more recent treatment.[footnote 7] Similarly, responses to the first dose of vaccine were higher for patients with solid cancers who had not received chemotherapy within 15 days of vaccination compared to those who had.[footnote 8] This data suggests that a third dose given at an appropriate interval from a period of immunosuppression is likely to provide a better vaccine response. JCVI recognises that many persons who are immunosuppressed remain concerned regarding their risk of COVID-19 despite having received 2 doses of the primary vaccine schedule as currently advised. The potential for additional protection from a third primary dose is unknown at an individual level. While antibody levels may be measured, without a clear understanding of the correlates of protection against severe disease and the interaction of immune suppression with measured immune responses, clinical inferences based on the measurement of antibody levels in persons who are immunosuppressed are difficult. For instance, low antibody levels may not denote poor protection against severe disease; and conversely, high antibody levels in a person unable to generate a commensurate cellular response may not denote good protection against severe disease. Until more data is available, any provision of a third primary dose to persons who are immunosuppressed will draw on the assumption that a third dose is unlikely to confer significant harms or disadvantages, but may offer the possibility of benefit. These uncertainties in harms and benefits will need to be communicated as part of informed consent, and expectations regarding the value of a third primary dose taken into account.