Coronavirus (COVID-19) advice for people on the Highest Risk List: evidence review

Annex A - Vaccine Efficacy and Effectiveness in people on the Highest Risk List: Evidence Summary

12. Vaccine Efficacy: Annotated Bibliography

12.1 The following section is an annotated bibliography of relevant studies on vaccine efficacy that have informed the current Scottish Government COVID-19 Highest Risk policy. It includes brief summaries of the main findings and their key limitations. Limitations are factors or characteristics which may have influenced or impacted study findings in particular ways. Many studies in this annotated bibliography will have several limitations. This does not necessarily mean that the studies are fundamentally wrong. Instead, limitations highlight things readers should keep in mind when interpreting findings.

12.2 This is not a complete list of studies on vaccine efficacy for the Highest Risk List. It is only a list of studies that have informed Scottish Government policy. Readers should note that studies included in this list measure different things and this should be kept in mind when comparing findings between articles. For example, some studies have looked at vaccine efficacy after one dose only whereas others have looked at vaccine efficacy after two or three doses. The studies also use different methods and samples and this will also influence the findings. Please also note some of the studies referenced are pre-prints. This means they have not yet been peer-reviewed (evaluated for robustness by other academics in the same field) or published, and any findings should be considered more cautiously. Pre-prints have been highlighted where relevant.

13. Vaccine Efficacy and Effectiveness: Overview of annotated bibliography findings

13.1.1 Overall, the findings of the studies included suggest that vaccine efficacy for the Highest Risk List is not as high as for the general population, with a number of articles recommending booster and/or third doses as well as continued non-clinical safety measures (e.g. face masks and social distancing) to protect the health and wellbeing of more immunocompromised people.

13.1.2 Some studies have also looked at what characteristics are associated with increased risk for adverse COVID-19 outcomes, with several Highest Risk List subgroups highlighted as well as characteristics such as being older, male, or living in a care home.

13.1.3 A number of studies included here have also looked at differences between vaccine types (mainly AstraZeneca, Pfizer, and Moderna) but statistical significance testing has not been carried out in all studies which means any differences are at this stage only observed and it is not clear whether the differences are coincidental or not.

13.2 Agrawal, U., Vittal Katikireddi, S., McCowan, C., Mulholland, RH., Azcoaga-Lorenzo, A., Amele, S., Francis Fagbamigbe., A., Vasileiou, E., Grange, Z., Shi, T., Kerr, S., Moore, E., Murray, JLK., Ahmar Shah, S., Ritchie, L., O'Reilly, D., Stock, SJ., Beggs, J., Chuter, A., Torabi, F., Akbari, A., Bedston, S., McMenamin, J., Wood, R., Tang, RSM., de Lusignan, S., Hobbs, R., Woolhouse, M., Simpson, CR., Robertson, C., and Sheikh, A. (2021) 'COVID-19 hospital admissions and deaths after BNT162b2 and ChAdOx1 nCoV-19 vaccinations in 2.57 million people in Scotland (EAVE II): a prospective cohort study'.

The Lancet. Online First.

This national-level study looked at the frequency of COVID-19-related hospitalisations and deaths in people who had received at least one vaccine dose in Scotland and sought to establish what characteristics put people more at risk of hospitalisation or death based on this. The research period for this study was 8^th December 2020 to 18^th April 2021.

The study found that out of the 2,572,008 people who received their first vaccine dose during the study period, less than 0.1% were hospitalised or died due to COVID-19 14 days or more after vaccination.

The analysis also found that, after vaccination, COVID-19-related hospitalisation and death continued to be associated with:

• older age (≥80),
• having more than one comorbidity (more than one disease or condition present in the same person at the same time),
• being hospitalised in the previous four weeks,
• care home residence,
• socio-economic deprivation,
• being in a high-risk occupation (number of previous COVID-19 tests were used as a proxy for high-risk occupational groups who were repeatedly tested),
• being male,
• or being an ex-smoker.

Looking at people with multiple comorbidities, Agrawal et al. found that, for people who had been vaccinated, a history of:

• asthma,
• chronic kidney condition,
• heart failure,
• type 2 diabetes,
• dementia,
• or coronary heart disease

was associated with increased risk of hospitalisation or death.

The study suggested that, for those who had received the Pfizer vaccine, there was no association between increased risk of hospitalisation or death and asthma or heart failure. However, the study was unable to make robust comparisons between vaccines due to their differential use. This finding should therefore be considered cautiously.

13.3 Boyarsky, BJ., Werbel, WA., Avery, RK., Tobian, AAR., Massie, AB., Segev, DL., and Garonzik-Wang, JM. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA. 325(17).

This American study investigated immune responses following the first vaccine dose in solid organ (organs that are not hollow or liquid, such heart, liver, kidney, and lungs, among others) transplant recipients. The research period for this study was 16^th December 2020 to 5^th February 2021. Participants (n=436) were recruited via social media, meaning this study did not use a representative sample.

The study found that antibodies developed in 17% of participants 20 days after the first vaccine dose. The analysis also suggested that patients who were receiving anti–metabolite maintenance immunosuppression therapy (medication designed to prevent organ transplant rejections) were less likely to develop antibodies than those not receiving this therapy (37% vs 63%). Older transplant recipients were also less likely to develop antibodies. The study also suggested that those receiving the Moderna vaccine were more likely to develop antibodies than those receiving Pfizer (69% vs 31%).

A key limitation of this study is its convenience sample which means it may not apply to a wider population. The study also lacked a control group without immunosuppression, and it should also be noted the analysis is of responses to the first vaccine dose only. Despite these limitations, it was useful to highlight the potential issue caused by immunosuppression. This study suggested that vaccine efficacy was reduced in the solid organ transplant group.

13.4 Grange, Z., Buelo, A., Sullivan, C., Moore, E., Agrawal, U., Bouhkhari, K., McLaughlan, I., Stockton, D., McCowan, C., Robertson, C., Sheikh, A., and Murray, JLK. (2021) Characterisation and risk of COVID-19 related death in fully vaccinated people in Scotland. The Lancet. Online First

This national-level study sought to estimate the frequency of COVID-19-related deaths in fully vaccinated people in Scotland and to describe characteristics associated with this. This study looked at people who had been fully vaccinated (i.e. those who had had two vaccination doses) by 18^th August 2021. At the time of the study, there had been 236 COVID-19-related deaths in fully vaccinated people (those who had received at least 2 doses of vaccine)..

The study found most people who died after full vaccination were older than 75, with a median age of 80. The study also found that men had a higher risk of COVID-19 death than women, and that people with five or more comorbidities (more than one disease or condition present in the same person at the same time), were at substantially higher risk (although the confidence intervals for this were wide, which means the finding is uncertain).

As the study found that COVID-19-related deaths following vaccination were uncommon, there was only a small number of deaths to analyse, and findings should therefore be considered cautiously. The authors stressed the importance of continued caution and use of non-pharmaceutical interventions, particularly for older adults with multiple comorbidities. This study suggested that older people, men, and people with several pre-existing risk conditions were at increased risk of COVID-19 related death following vaccination.

13.5 Hall, VG. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. NEJM. 385(13)

This letter to the editor details the results of a double-blind randomised controlled trial (n=120) of a third dose of the Moderna vaccine compared with a placebo in transplant recipients. This study was carried out between 25^th May and 30^th August 2021.

The study found that a third dose of the Moderna vaccine in transplant recipients had a substantially higher antibody response than the placebo. 55% of the third dose group (n=60) had the study design's pre-requisite antibody level after four months, compared to 18% of the placebo group (n=57). The author recommends that a third-dose booster vaccine dose should be considered for transplant recipients who have received two doses of Moderna.

This study had a relatively small sample size and the author acknowledges the pre-requisite antibody level set was arbitrary and not necessarily predictive of protection from infection. This article suggested that a third dose of the Moderna vaccine had a benefit in increasing immune (antibody) responses for transplant recipients.

13.6 Hippisley-Cox, J., Coupland, CAC., Mehta, N., Keogh, RH., Diaz-Ordaz, K., Khunti, K., Lyons, RA., Kee, F., Sheikh, A., Rahman, S., Valabhji, J., Harrison, EM., Sellen, P., Haq, N., Semple, MG., Johnson, PWM., Hayward, A., and Ngyen-Van-Tam, JS. (2021) 'Risk prediction of COVID-19 related death and hospital admission in adults after COVID-19 vaccination: national prospective cohort study'. BMJ. 374 (2244).

This national-level study analysed COVID-19-related hospitalisations and deaths after vaccination in England in order to identify risk factors. The study period for this project was 8^th December 2020 to 15^th June 2021. The study included people who had only one vaccine dose as well as those who had had both doses.

Analysis identified the highest risks for COVID-19-related mortality as being associated with:

• Down's syndrome
• kidney transplants
• sickle cell disease
• living in care homes
• chemotherapy
• ever having had a solid organ transplant
• having recently had a bone marrow transplant
• HIV/AIDS
• dementia
• Parkinson's Disease
• neurological conditions
• liver cirrhosis

It also found COVID-19 mortality increased with:

• age and deprivation
• being male
• being of Indian and Pakistani ethnic origin

The trends for COVID-19 related hospitalisations were similar. It should be noted that numbers for some of the subgroups were small. In addition to this, most of the data was based on only one vaccine dose, with a relatively small proportion of COVID-19 deaths occurring in those who had had both vaccine doses.

There was also a lack of data on younger people without underlying conditions due to the prioritisation of the national vaccine roll-out. This study suggested that there was a higher risk of COVID-19 related death or hospitalisation following at least one vaccination dose for people who:

• had relevant pre-existing medical conditions that make them more vulnerable to hospitalisation or death from COVID-19
• were older
• lived in more deprived areas
• were of Indian or Pakistani origin

13.7 Kearns, P., Siebert, S., Willicombe, M., Gaskell, C., Kirkham, A., Pirrie, S., Bowden, S., Magwaro, S., Hughes, A., Lim, Z., Dimitriadis, S., Murray, SM., Marjot, T., Win, Z., Irwin, SL, Meacham, G., PITCH Study Group, OCTAVE Study Group, Alex G. Ritcher, Kelleher, P., Satsangi, J., Miller, P., Rea, D., Cook, G., Turtle, L., Klenerman, P., Dunachie, SJ., Basu, N., de Silva, TI., Thomas, D., Barnes, E., Goodyear, CS., and McInnes, I . Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity – the OCTAVE Trial. PRE-PRINT. Accessed on 4^th November 2021.

NB. This study is a pre-print and has not been peer-reviewed. Findings should therefore be considered cautiously until it has been appropriately reviewed and approved for publication.

The OCTAVE trial is a national-level study into vaccine responses within and between different disease cohorts from across the UK. This paper reports on analysis based on the first 655 patients as of 13^th August 2021 and also includes data from 231 healthy individuals as a control group.

The study found that 89% of patients with less good immune systems produced antibodies after vaccination, compared to 100% of tested healthy individuals. People with particular conditions were less likely to produce antibodies, e.g. ANCA-Associated Vasculitis (72%), end stage kidney disease requiring haemodialysis with immunosuppression (17%), and hepatic disease (17%).

Of the patients that did produce antibodies after vaccination, 40% across the different disease cohorts still produced lower levels of antibodies than the healthy subjects. However, it should be noted that the tested healthy subject sample was relatively small (n=93).

There were various limitations to this study, including not carrying out formal statistical comparison between groups, an inability to obtain baseline data on all participants, disease group sizes being unequal, and the control group and disease cohort samples were not equivalent in terms of both gender and age, so comparisons of outcomes may not be accurate.

This study suggested that immunocompromised people were less likely to produce an immune response to the COVID-19 vaccine than the general population and were also more likely to produce a lower response.

13.8 McKeigue, PM., McAllister, DA., Bishop, J., Hutchinson, S., Robertson, C., Lone, N., McMenamin, J., Goldberg, D., and Colhoun, HM. et al (2021) Efficacy of COVID-19 vaccination in individuals designated as clinically extremely vulnerable in Scotland [version 1; peer review: 1 not approved]. F1000Research 10(663). PRE-PRINT. Accessed 5^th November

NB. This study is a pre-print and has not been peer-reviewed. Findings should therefore be considered cautiously until it has been appropriately reviewed and approved for publication.

This matched case-control study estimated vaccine efficacy in reducing the risk of severe COVID-19 (defined as entry to critical care or death) in people designated clinically extremely vulnerable in Scotland. The study period for this research was 1^st December 2020 to 16^th March 2021.

The study found that the efficacy of a single vaccination dose against severe COVID-19 was as high for people designated as clinically extremely vulnerable as for those who were not. However, this study is limited by small numbers of data for specific risk conditions, especially for solid organ transplant recipients who are at highest risk. The study was therefore unable to reliably estimate the vaccine efficacy for transplant recipients.

This study suggested vaccine efficacy was as high for those who were clinically extremely vulnerable as for the general population, but did not reliably take into account vaccine efficacy for transplant recipients and other specific risk conditions.

13.9 McKeigue, PM., McAllister, DA., Hutchinson, SJ., Robertson, C., Stockton, D., and Colhoun, HM. (2021)Efficacy of vaccination against severe COVID-19 in relation to Delta variant and time since second dose: the REACT-SCOT case-control study.PRE-PRINT – Accessed 3 November 2021

NB. The study linked is a pre-print and had not been peer-reviewed at time of writing. Findings should therefore be considered cautiously until it has been appropriately reviewed and approved for publication.

This national-level case-control study investigated vaccine efficacy against severe COVID-19 (defined as entry to critical care or death) since the Delta variant became dominant in Scotland, and looked at whether vaccine efficacy waned with time. The study considered all diagnosed cases of COVID-19 in Scotland up to 19 August 2021.

The study found that the replacement of the Alpha variant by the Delta variant as the dominant COVID-19 variant in Scotland in May 2021 was accompanied by a temporary reduction of vaccine efficacy against severe COVID-19. This finding does not suggest that vaccines are less effective for the Delta variant, however it should be noted that authors did not have a direct measurement for variant types and instead looked at the time windows for replacement of the Alpha variant by the Delta variant.

The study also showed that two doses of AstraZeneca was 91% effective against severe disease, however this decreased to 69% at 20 weeks from the second dose. The efficacy for Pfizer and Moderna was measured as 92%, declining in the first ten weeks after second dose to then stabilise at around 90%.

Based on these findings, authors recommend that booster vaccine doses should initially focus on those who received the AstraZeneca vaccine. The authors note that the findings may be affected by a seasonality bias as analysis is based on cases between May 2021 and August 2021. This means that the findings may not be accurate for other times of year. This study suggested that COVID-19 vaccines are effective against the Delta variant, and that the AstraZeneca vaccine efficacy decreases substantially with time after the second dose.

13.10 McKeigue, PM., McAllister, DA., Robertson, C., Hutchinson, S., McGurnaghan, S., Stockton, D., and Colhoun, HM. Efficacy of two doses of COVID-19 vaccine against severe COVID-19 in those with risk conditions and residual risk to the clinically extremely vulnerable: the REACT-SCOT case-control study.PRE-PRINT. Accessed 4 November 2021.

NB. This study is a pre-print and has not been peer-reviewed. Findings should therefore be considered cautiously until it has been appropriately reviewed and approved for publication.

This national-level study sought to determine whether the efficacy of the COVID-19 vaccine varied with clinical risk categories as well as to investigate the risk factors for severe COVID-19 (defined as cases with entry to critical care or death) after receiving two vaccine doses in Scotland. The study period for this research was 1^st December 2020 to 19^th August 2021.

The study found that vaccine efficacy against severe COVID-19 following two vaccine doses was 73% for those designated as clinically extremely vulnerable, compared to 89% for those with moderate risk conditions and 94% for people without risk conditions.

The study also found that, among the double-vaccinated population at time of analysis, those with designated risk conditions or who are clinically extremely vulnerable accounted for 85% of severe cases and 75% of hospitalised cases. It should be noted that this refers to small numbers of deaths and hospitalisations – at the time of study there had been 81 deaths and 71 hospitalisations in the fully vaccinated population (n= 5,150,310) at least 14 days after vaccination.

The study findings suggested that solid organ transplant patients were most at risk of severe disease out of the double-vaccinated clinically extremely vulnerable group, but authors noted that even in this subgroup the absolute risk of severe COVID-19 was low. Numbers for some of the clinically extremely vulnerable groups were small. The authors recommended passive immunisation therapies for solid organ transplant recipients and suggested a booster-dose for added protection. This study suggested vaccine efficacy was lower for those who were clinically extremely vulnerable and those who had moderate risk conditions compared to people without risk conditions.

13.11 Prendecki, M., Thomson, T., Clarke, L., Martin, P., Gleeson, S., Cardoso De Aguiar, R., Edwards, H., Mortimer, P., McIntyre, S., Mokreri, D., Cox., A., Pickard., G., Lightstone. L., Thomas, D., McAdoo, SP., Kelleher, P., and Willicombe, M. (2021) 'Immunological responses to SARS-CoV-2 vaccines in kidney transplant recipients'. The Lancet. 398(10310).

This study investigated antibody responses to two doses of the Pfizer and AstraZeneca vaccines in two groups of kidney transplant recipients (n=920 and n=106) and one group of healthcare workers (n=65).

The study found that people who had not had COVID-19 and who received the Pfizer vaccine were more likely to produce antibodies and develop higher levels of antibodies in the blood compared to patients receiving AstraZeneca. It also found that the immune (antibody) responses in transplant recipients were significantly weaker than those seen in health-care workers. As the study cohorts were imperfectly matched both in terms of size and other characteristics such as age, this conclusion should be considered with caution, which is acknowledged by the authors. The study recommended that kidney transplant patients' household members should be immunised and that patients should be educated to maintain physical distancing rules. This study suggested that vaccine efficacy was not as high for kidney transplant recipients as for health care workers who had not had transplants.

13.12 Sheikh, A, Kerr, S, Woolhouse, M, McMenamin, J & Robertson, C. (2021) Severity of Omicron variant of concern and vaccine effectiveness against symptomatic disease: national cohort with nested test negative design study in Scotland. PRE-PRINT. Accessed 25 February 2022.

NB. This study is a pre-print and has not been peer-reviewed. Findings should therefore be considered cautiously until it has been appropriately reviewed and approved for publication.

This national-level study used the Early Pandemic Evaluation and Enhanced

Surveillance of COVID-19 (EAVE II) Scotland-wide prospective cohort to estimate hospital admissions associated with omicron and vaccine effectiveness against symptomatic disease with the omicron variant. The analysis covered the period from 1^st November to 21^st December 2021.

The study estimated that the Omicron variant was substantially less likely to result in COVID-19 hospitalisation than Delta. It also found that a third/booster dose of a COVID-19 vaccine offered substantial additional protection against symptomatic disease within two weeks of this additional dose, compared to two doses of vaccine received 25 or more weeks ago. This protection was greatest for Delta, but still substantial for Omicron.

The study had a number of limitations. Firstly, challenges with the data meant that the study was unable to establish the effectiveness of the vaccine in protecting against symptomatic disease for those who tested positive for COVID-19 in hospital settings. Secondly, the study assumed that the length of time between contracting COVID-19 and ending up in hospital because of COVID-19 would be the same for both the delta and omicron variants.

The low number of hospital admissions for COVID-19 during the study period made it difficult to accurately predict future hospital admission rates from the available data. Finally, there is also a possibility that the effectiveness of the vaccine would wane over time for certain groups in the population. The timing of this study meant that the research was unable to assess this.

13.13 Sheikh, A., McMenamin, J., Taylor, B., and Robertson, C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. The Lancet. 397(10293).

This national-level study explored the risk of hospitalisation for COVID-19, estimated vaccine effectiveness in preventing COVID-19 hospitalisation and described the demographic profile of COVID-19 patients. It also looked at differences according to COVID-19 variant. The analysis covered the period from 1^st April to 6^th June 2021.

The study found that for the whole population cohort, the Pfizer vaccine offered very good protection at least 14 days after the second dose (92% for the Alpha variant, and 79% for the Delta variant). The AstraZeneca vaccine was also protective but with reduced effect (73% for the Alpha variant, and 60% for the Delta variant).

However, the study did not test whether the difference between vaccines was statistically significant, so the finding should be considered cautiously. The study also found that the Delta variant was found mainly in younger, more affluent groups, and that the risk of COVID-19 hospitalisation approximately doubled in those with the Delta variant compared to those with the Alpha variant, with the risk of hospitalisation particularly increased in those with five or more relevant comorbidities (more than one disease or condition present in the same person at the same time).

This study suggested that vaccines offered good protection for the general population as a whole against COVID-19 related hospitalisation.