Independent report

Pre-exposure prophylaxis (PrEP) report

Published 31 March 2023

Applies to England

Background

This report is about the use of COVID-19 directed antibodies in prophylaxis settings in patients who are immunologically vulnerable and at risk of adverse outcome in the event of SARS-CoV-2 infection. ‘Adverse outcome’ here includes hospitalisation and death.

The research is by an independent advisory group (IAG) and concerns the use of neutralising monoclonal antibodies (nMABs) and antiviral drugs in highest-risk clinical subgroups upon community infection with SARS-CoV-2.

This report was updated on 31 March 2023. The original version of the report can be found on pages 972 to 987 of the ‘Committee papers’ available on the National Institute for Health and Care Excellence (NICE) webpage Tixagevimab plus cilgavimab for preventing COVID-19 [ID6136]. It was produced in July 2022 and was submitted to NICE as part of their health technology evaluation of Evusheld.

Description of approach taken by the independent advisory group (IAG)

This IAG was previously put together to identify a set of patient conditions (or cohorts) that are deemed to be at the very highest risk of an adverse COVID outcome. The advisory group was asked to:

• generate a list of conditions or cohorts in order of greatest risk
• identify a clinically useful list of people with such conditions that might, by way of clinical advantage, render them recipients of nMABs prophylaxis

The advisory group was formed under terms of reference described in Higher-risk patients eligible for COVID-19 treatments: independent advisory group report to the Chief Medical Officer which we have recently updated (Higher-risk patients eligible for COVID-19 treatments: independent advisory group report (March 2023)).

The group is made up of a range of academics with requisite clinical and scientific expertise, some of whom had participated previously in the COVID-19 nMABs Access and Policy National Expert Group. Particular attention was paid to develop a diverse and inclusive set of participants to represent the clinical subgroups that required consideration based on the prior recommendations of the COVID-19 nMABs Access and Policy National Expert Group.

For this update, the group has been further extended to properly reflect the range of conditions now identified to confer high risk of poor outcomes upon SARS-CoV-2 infection and in whom sub-optimal vaccine efficacy might be anticipated.

Meetings were held online through video conferencing between December 2022 and January 2023. Additional interactions took place electronically to derive consensus statements. All were chaired by Professor Iain McInnes, University of Glasgow.

Overarching principles agreed by the independent advisory group

For this report we took the same approach as that adopted previously. This is summarised briefly as follows:

The IAG group originally used the QCOVID risk stratification tool - the QCOVID risk stratification tool is a population-based cohort record linkage study that used primary care data to derive and validate risk prediction algorithms to estimate risk of COVID-19 mortality and hospitalisation in UK adults following one or two doses of COVID-19 vaccination.

In addition, it evaluated additional input from the ISARIC Coronavirus Clinical Characterisation Consortium. The advisory group accepted the principle previously established that once risk magnitude was established for a given condition or set of conditions, consideration was given to clinical capacity to benefit from introduction of nMAB, or of an antiviral, now applied in a prophylactic setting - that being in a patient deemed at higher risk but in whom there is no active infection.

In this update we evaluated papers published or in pre-print format, in the general and discipline specific literature, made available through to 1 December 2022 that might alter or confirm our 2 prior recommendations (offered to the Department of Health and Social Care (DHSC) in draft form). In particular, we evaluated data contained in public health datasets (for example, Agrawal and others, Lancet 2022; OpenSAFELY Collaborative) that identified conditions in which poorer outcomes were likely, and also the update to the QCOVID risk tool programme that originally significantly informed the work of the IAG in its first deliberations, namely QCOVID4, to provide evidence of poorer outcomes in conditions included in our original report but also conditions not originally covered by the remit of the IAG.

We further evaluated the literature that has examined the immunologic efficacy of SARS-CoV-2 directed vaccines in patients in whom a sub-optimal or absent vaccine response might be anticipated, particularly those with compromised immunity. Several immunological efficacy studies have clearly identified vaccine ‘failures’ (absent response despite numerous boosts) or partial response (defined arbitrarily as detectable serology responses that is lower than the lowest seen in comparable healthy control populations) in diagnostic groups and/or therapeutic recipients - these are primarily laid out in group A2. In principle, the diagnostic or therapeutic groups mounting sub-optimal vaccine responses, that are also at high risk of poor outcome, comprise that group most likely to benefit from nMAB prophylaxis. We consider that other patient groups that are at high risk of poor outcome, yet are fully immune competent, may not benefit from prophylaxis as they already have high levels of neutralising anti-SARS-CoV2-2 antibody. By corollary, their capacity to benefit from nMAB prophylaxis would be lower.

The advisory group considered the potential for serology to support decision-making. There are currently reported populations and observational studies defining the potential for levels of protection afforded by serology levels, and several pre and post-vaccine immunophenotyping studies in patient subgroups at special risk. For example, the Medicines and Healthcare products Regulatory Agency (MHRA) approved ongoing OCTAVE, OCTAVE-DUO studies that might inform the use of such testing. (OCTAVE-DUO is a prospective, multicentre, multi-disease, randomised trial to determine whether a re-boost vaccine strategy can induce an immune response in clinically vulnerable patients who have not produced an adequate antibody response after 2 doses of COVID-19 vaccine.) There are, however, no studies that have offered a definitive serology ‘level’ that defines protection against native infection in a real-life setting. There is evidence from the UK COVID Cancer programme that very low or absent levels confer higher levels of risk in cancer patients, but this requires validation.

Moreover, given the propensity for viral evolution by mutation and thereby altered levels of immune protection afforded by any given level of anti-S antibody specific for any given variant, we do not herein offer a specific recommendation around the use of serology testing. Further work, including ex vivo and clinical studies, are recommended in this area to inform policy.

The IAG remains agnostic to any individual nMAB product and makes no cross comparisons as to a preferred product.

As before, the IAG recognised that most current evidence and some approvals of existing agents apply to individuals aged 18 and over - nevertheless we have offered advisory notes to advise as appropriate approvals for use emerge for individuals aged less than 18 years. Given the substantially lower risk of severe disease in this age group, clinician discretion is advised for groups A1, A2 and B, and the presence of multiple co-morbidities in addition to primary risk diagnoses may be required to reach the threshold for use of prophylactic treatments.

Recommendations concerning pre-exposure prophylaxis

Summary

The following recommendations should be read as a prioritised list.

1. Group A contains those conditions for which we consider there is high priority for prophylaxis (but note that, in some instances, prophylaxis may already be effectively achieved - for example, via the administration of immunoglobulin replacement therapy - see point 2 in explanatory notes below).

2. Group B defines a group of conditions in which consideration of prophylaxis might be given and which may be influenced by other co-morbidities - for example, obesity, age, or definition of their serology status if this becomes available as a usable clinical entity.

3. Group C defines conditions in which prophylaxis is unlikely to be of added value as we anticipate immune competence upon exposure to vaccination.

Group A1: known failure of vaccination

This group includes:

• any person in any risk group unable to complete vaccination schedule according to contemporaneous recommendations^{[footnote 1]}

• any person in any risk group with one or more admissions due to moderate or severe COVID-19 despite completing recommended vaccinations

Group A2: anticipated failure of vaccination

This group includes:

• primary immunodeficiencies with impairment of antibody production^{[footnote 2]}
• any person with secondary immunodeficiency receiving, or eligible for, immunoglobulin replacement therapy (but see point 2 in explanatory notes below)
• any person receiving anti-CD20 monoclonal antibodies or other B-cell depleting therapy (including anti-thymocyte globulin (ATG) and alemtuzumab) within the last 12 months
• allogeneic haematopoietic stem cell transplant (HSCT) recipients in the last 12 months or active graft versus host disease (GVHD) regardless of time from transplant (including HSCT for non-malignant diseases)
• autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases)
• individuals who have received CAR-T cell therapy in the last 24 months, or until the lymphocyte count is within the normal range
• all people with myeloma (excluding monoclonal gammopathy of unknown significance (MGUS) or chronic B-cell lymphoproliferative disorders (for example, chronic lymphocytic leukaemia, follicular lymphoma) or myelodysplastic syndrome (MDS), or chronic myelomonocytic leukaemia (CMML) or myelofibrosis, who do not fit the criteria above
• solid organ transplant recipients

Group B: anticipated sub-optimal vaccination response: physician discretion advised

This group includes:

• any person with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months
• individuals with any mature T-cell malignancy
• people on conventional immunosuppressive therapy or who have received treatment with conventional immunosuppressive therapy within the last 3 months
• people on biologics^{[footnote 3]} or small molecule JAK-inhibitors (except anti-CD20 depleting monoclonal antibodies) or who have received these therapies within the last 6 months
• people who have received radiotherapy in the last 6 months
• people who have received group B or C chemotherapy regimens in the last 12 months
• people with a current solid organ malignancy, regardless of treatment
• people with chronic kidney disease (CKD) 4 or 5
• people with liver cirrhosis (Child-Pugh A, B and C cirrhosis)
• people receiving chronic high-dose corticosteroid therapy: greater than 10mg prednisolone (or equivalent) per day for more than 4 weeks, or who completed a course of high-dose corticosteroid therapy lasting at least 4 weeks within the last 3 months
• allogeneic or autologous stem cell transplant recipients beyond 12 months and without active GVHD
• people with uncontrolled or clinically flaring immune mediated inflammatory disorders (IMIDs)
• people with HIV infection with CD4 less than 200 cells/mm³ or not on treatment or evidence of failure on treatment

Group C: anticipated good vaccination response - unlikely to require prophylaxis unless co-morbid with other immunological risk factors ^{[footnote 4]}

This group includes people:

• with Down’s syndrome
• with sickle cell disease, thalassaemia or other inherited anaemia
• with diabetes and cardiovascular disease unless with demonstrably absent or low vaccine serology response
• living with HIV stable on treatment (suppressed viral load) with CD4 greater than 200
• with chronic neurological conditions not receiving anti-CD20 therapy ^{[footnote 5]}

Explanatory notes and research requirements

1. Since a significant proportion of people in the priority groups will be capable of mounting a detectable antibody response to vaccination, a SARS-CoV-2 serological test, standardised across different platforms, with clear correlation to clinical protection, could be useful to guide prophylaxis decisions and should be pursued as a priority. If a recent anti SARS-CoV-2 spike antibody result is available, clinicians may wish to use this to help guide individual treatment decisions (for example, a decision to administer prophylaxis if the antibody response is absent). However, no reliable serology level has yet been established for currently available tests, and the informative value of such tests may vary with emerging variants. We do not currently recommend a serology level for wide adoption. This is an area requiring active research.

2. Clinicians should be aware that not all patients with immunodeficiency would benefit from pre-exposure prophylaxis. There is now well-validated evidence of the presence of significant concentrations of SARS-CoV-2 anti-spike antibody levels in most commercial preparations of polyclonal therapeutic immunoglobulin as a result of vaccination and natural infection in the donor plasma pool. These levels approach or exceed levels of antibodies present in convalescent plasma and hyperimmune globulin and exhibit neutralising antibody titres comparable to those found in healthy controls.^{[footnote 6]} Decisions on eligibility for pre-exposure prophylaxis in individual patients should, therefore, take into consideration the passive protection provided by anti-spike antibodies in patients on maintenance replacement immunoglobulin.

3. The decision to administer pre-exposure prophylaxis to an individual should be regularly reviewed taking into account changes in treatment, disease status, vaccination recommendations and COVID-19 epidemiology.

4. Consideration should be given to waning immunity which may differ among groups.

5. Although severe COVID-19 is uncommon in children and young people, children under one year of age are more likely to be admitted to hospital than other age groups. Predisposing factors for severe disease in this age group include age 0 to 3 months, prematurity and co-morbidities including immunocompromise and pulmonary disease (in particular, a baseline oxygen requirement). On the basis of the currently available evidence, and in the absence of an available SARS-CoV-2 vaccine for children under 5 years of age, if licensed, pre-exposure prophylaxis with a long-acting monoclonal antibody could be recommended as follows:

• children under 9 months of age with chronic lung disease (defined as requiring oxygen for at least 28 days from birth) and who were born preterm
• children under 6 months of age with haemodynamically significant, acyanotic congenital heart disease who were born preterm

It may also be considered for:

• children under 1 year of age who require long-term ventilation
• children 1 to 2 years of age who require long-term ventilation and have an additional co-morbidity (including cardiac disease or pulmonary hypertension)

Appendix 1: members of the advisory group

• Professor Iain McInnes (Chair), Vice Principal and Head of College, College of Medical, Veterinary and Life Sciences, University of Glasgow

• Professor Anthony Kessel (supporting), Clinical Director National Clinical Policy, Specialised Commissioning NHS England and Improvement

• Professor Benedict Michael, Professor of Neuroscience and Honorary Consultant Neurologist, NIHR Health Protection Research Unit for Emerging and Zoonotic Infection, University of Liverpool

• Professor Baba Inusa, Chair, National Haemoglobinopathy Panel, England; Professor of Paediatric Haematology and Sickle cell disease, Guy’s and St Thomas’ NHS Foundation Trust

• Professor Carl Goodyear, Professor of Translational Immunology, University of Glasgow

• Professor Calum Semple, Professor of Child Health and Outbreak Medicine at University of Liverpool, and Consultant Respiratory Paediatrician at Alder Hey Children’s NHS Foundation Trust, Liverpool

• Professor Carlo Palmieri, Professor of Translational Oncology and Medical Oncologist, Molecular and Clinical Cancer Medicine, University of Liverpool

• Professor Claire Harrison, Professor of Myeloproliferative Neoplasm, Guy’s and St Thomas’ NHS Foundation Trust

• Dr Charlie Tomson, Consultant Nephrologist, North Bristol NHS Trust

• Dr David Lowe, Consultant Clinical Immunologist, Royal Free Hospital

• Dr Dhivya Subramaniam (supporting), National Clinical Policy Fellow, NHS England and NHS Improvement

• Professor Eleanor Barnes, Professor of Hepatology and Experimental Medicine, Nuffield Department of Medicine, University of Oxford, Oxford University Hospitals NHS Foundation Trust

• Dr Elizabeth Whittaker, Honorary Clinical Senior Lecturer, Faculty of Medicine, Department of Infectious Disease, Imperial College London

• Professor Emma Thomson, Professor in Infectious Diseases, University of Glasgow

• Dr Edward Carr, Post-doctoral Clinical Fellow, The Francis Crick Institute,

• Dr Emily Padfield, NHS England (Supporting)

• Professor Gary Middleton, Professor of Medical Oncology, University of Birmingham

• Professor Jack Satsangi, Professor of Gastroenterology, University of Oxford

• Professor Julia Hippisley-Cox, Professor of Clinical Epidemiology and General Practice, Chair, COVID Risk Stratification Subgroup, NERVTAG

• Dr Josh Wright, Consultant Haematologist, Sheffield Teaching Hospitals NHS Foundation Trust; Lead Clinician, North East and Yorkshire Haemoglobinopathy Coordinating Centre

• Dr Jane Collier, Consultant Hepatologist, Oxford University Hospitals NHS Foundation Trust

• Professor Kwee Yong, Professor of Clinical Haematology, University College London Hospitals

• Dr Katie Vinen, Kings College Hospital NHS Foundation Trust

• Dr Laurie Tomlinson, Consultant Nephrologist, London School of Hygiene and Tropical Medicine

• Professor Lennard Lee, Honorary Senior Research Fellow, Institute of Cancer and Genomic Sciences, University of Birmingham

• Dr Lisa Spencer, Consultant Respiratory Physician, Liverpool University Hospitals NHS Foundation Trust

• Professor Lucy Wedderburn, Professor in Paediatric Rheumatology, University College London

• Professor Martin Underwood, Professor of Primary Care Research, Warwick Clinical Trials Unit, Warwick Medical School

• Dr Matthias Schmid, Consultant Physician and Head of Department, Infection and Tropical Medicine, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, and Chair, Clinical Reference Group Infectious Diseases, NHS England

• Professor Matthew Snape, Professor in Paediatrics and Vaccinology, Oxford Vaccine Group

• Professor Martin Turner, Professor of Clinical Neurology and Neuroscience, Nuffield Department of Clinical Neurosciences, University of Oxford, and Honorary Consultant Neurologist, Oxford University Hospitals NHS Foundation Trust

• Dr Michelle Willicombe, Consultant Nephrologist, Imperial College Healthcare NHS Trust,

• Dr Nick Kennedy, Consultant Gastroenterologist, University of Exeter

• Dr Nick Powell, Consultant Gastroenterologist, Imperial College London

• Professor Paul Moss, Professor of Haematology, University of Birmingham

• Dr Paul Cockwell, Consultant Physician, University Hospital Birmingham

• Dr Rupert Beale, Immunologist and Clinical Nephrologist, and Clinical Researcher, Crick Institute

• Dr Siraj Misbah, Consultant Immunologist and Chair, Blood and Infection Programme of Care, NHS England

• Professor Stefan Siebert, Professor of Inflammation Medicine and Rheumatology, University of Glasgow

• Dr Sean Lim, Associate Professor and Honorary Consultant in Haematological Oncology, University of Southampton

• Dr Stephen McAdoo, Consultant Nephrologist, Imperial College London

• Professor Thushan de Silva, Professor and Honorary Consultant Physician in Infectious Diseases, University of Sheffield

• Professor Tariq Ahmed, Consultant Gastroenterologist, University of Exeter

• Dr Tom Marjot, Clinical Fellow in Hepatology, Oxford University Hospitals NHS Foundation Trust

• Professor Chris Griffiths, Dermatology, University of Manchester

• Professor Richard Warren, Dermatology, University of Manchester

1. People who have not yet completed their vaccination schedule should, wherever possible and appropriate, receive the necessary vaccinations in preference to commencing pre-exposure prophylaxis. ↩

2. Primary immunodeficiencies:

   a. common variable immunodeficiency (CVID)

   b. undefined primary antibody deficiency on immunoglobulin (or eligible for Ig)

   c. hyper-IgM syndromes

   d. Good’s syndrome (thymoma plus B-cell deficiency)

   e. severe combined immunodeficiency (SCID)

   f. x-linked agammaglobulinaemia (and other primary agammaglobulinaemias) ↩

3. People on monotherapy with biologics as maintenance therapy in IMIDs (including anti-IL17A, anti-IL-6R, anti-BLyS, anti-TNF, anti-IL12/23, vedolizumab and abatacept) appear not be at significantly increased risk of severe COVID-19 on available evidence. Physician discretion is advised in the context of patients in receipt of combination immune modification. ↩

4. Patients in this category are assumed not to have a condition in groups A or B that would confer a different clinical decision. ↩

5. The IAG notes a theoretical concern in patients with rare neurologic demyelinating syndromes attributed to autoantibodies (or other immune mechanisms) arising as a result of COVID-19. This requires further evaluation. ↩

6. Karbiener and others, J Infect Dis 2021;224: 1707-11; Farcet and others, J Infect Dis 2022; 226:1396-1400; Hirsiger and others, J Allergy Clin Immunol Pract 2022; In press; Upasani and others, MedRxIV. ↩