Independent report

Chapter 9: pharmaceutical interventions: therapeutics and vaccines

Updated 10 January 2023

Introduction

In the first weeks and months of the COVID-19 pandemic no evidence-based therapeutic options (drugs) or vaccines were available, and there was uncertainty about which existing treatments should be prioritised for clinical trials and where research efforts should be focused to develop novel therapeutics and vaccines. Procurement of potential treatments was challenging, with rapidly changing and competitive global markets and a need to act fast with very limited data. These needs were addressed through collaboration between the NHS, funders, academia, the pharmaceutical industry and the general public.

This chapter sets out the experience in researching, developing and deploying therapeutics and vaccines in the COVID-19 pandemic in the UK. The science behind research, development and manufacturing of COVID-19 medical countermeasures was global, and will be in any future pandemic. The UK was, however, a significant contributor to the evidence base in COVID-19, and relying on others rather than instigating research would have led to significant delays in the deployment of several countermeasures in the UK and globally.

Research

General principles on research in the UK effort are given in Chapter 3: research.

Early in the pandemic, the World Health Organization (WHO) and major drug regulators highlighted the situation in previous epidemics (such as SARS-CoV-1 and Ebola virus) in which a multitude of small trials provided no meaningful new knowledge, or where large quantities of unproven treatments were given to patients outside the context of clinical trials. They emphasised the need for a relatively small number of large, randomised trials comparing the effects of possible therapeutic options with usual care alone.

The UK followed this approach, and a jointly funded National Institute for Health Research (NIHR) and UK Research and Investment (UKRI) Medical Research Council (MRC) rapid call for research into vaccines and therapeutics was launched on 4 February 2020, 4 days after the first UK case.^{[footnote 1]}

Strong existing research infrastructure (especially NIHR, MRC and UKRI) was important for the rapid start-up of research, as were linked data systems, which built on learning from the 2009 H1N1 influenza or ‘swine flu’ pandemic and subsequent independent review of governmental response. The start-up of all NIHR-supported non-COVID-19 studies was temporarily paused. Resumption as soon as feasible was encouraged, recognising the lifesaving treatment clinical trials can offer (such as oncology therapies), although this proved harder than anticipated.

There was also early direction to clinicians in the form of a UK CMO letter (1 April 2020, see Appendix A: examples of public letters and statements from UK CMOs) to the NHS to prioritise recruitment to highest priority clinical trials, and to desist from prescribing unproven off-licence drugs outside of trials.^{[footnote 2]} While both in theory and in retrospect this was sensible, at the time it was controversial as clinicians had no proven COVID-19 therapeutics options.

Trials were set up as early as possible and in advance of the UK’s first wave. COVID-19 clinical trials were embedded as a core component of NHS care, with data collection and surveillance of patients continuing following treatment and discharge – for example, to capture incidence of long-term side effects and survey for emerging drug resistance where possible. Generally, the UK was stronger on phase 3 and 4 trials than on phases 1 and 2.

Observational studies provided key evidence on the impact of vaccines and pharmaceuticals throughout the pandemic, often ahead of results from clinical trials. For example, the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) provided early reports of complications and treatment outcomes reported in hospitalised patients through analysis of data of over 70,000 patients recruited through their COVID-19 Clinical Information Network (CO-CIN).^{[footnote 3]} CO-CIN built on the inFLUenza Clinical Information Network (FLU-CIN) established during the 2009 to 2010 H1N1 influenza pandemic, and it provided the first open-access comprehensive clinical–epidemiological data at scale in this pandemic, reporting weekly to the Department of Health and Social Care (DHSC) and the Scientific Advisory Group for Emergencies (SAGE).

Similarly, the SARS-CoV-2 immunity and reinfection evaluation (SIREN) study, a large, national, multicentre prospective cohort study conducting serial asymptomatic SARS-CoV-2 testing of NHS workers, provided some of the earliest real-world estimates of vaccine effectiveness and reinfection rates in the working age population.^{[footnote 4]} The Vivaldi study investigated SARS-CoV-2 transmission, infection outcomes and immunity in residents and staff care homes in England, providing information on the impact of booster and primary vaccination on immunity and transmissibility in older age groups and in this vulnerable setting.^{[footnote 5]}

From the outset a 4-nation joint approach was taken to leadership, research, governmental delivery and procurement in therapeutics and vaccines. This combined resource facilitated faster and more diverse trial recruitment, supported equity of access for therapeutics, and strengthened the UK’s negotiating position in a globally competitive market.

Therapeutics development and research

Based on emerging knowledge of SARS-CoV-2 and the pathophysiology of similar viruses (both of which are outlined in Chapter 1: understanding the pathogen), potential pharmaceutical agents fell broadly into 3 categories:

• those with direct activity against SARS-CoV-2 (in other words, direct-acting antiviral agents)
• those modulating the host immune response to the pathogen such as monoclonal antibodies targeting a specific cytokine (such as TNF inhibitors, IL-1 inhibitors) or corticosteroids (such as dexamethasone)
• those modulating other organ system responses to the pathogen (such as renin-angiotensin, aldosterone and antithrombotic activities)^{[footnote 6]}, ^{[footnote 7]}, ^{[footnote 8]}

Identifying candidates for clinical trials

There was an initial need to rapidly identify existing drugs that could be safely and effectively repurposed. Hundreds of candidate therapeutics were proposed in the first days and weeks of the pandemic, and prioritisation was necessary to maximise use of limited resources and ensure adequately powered clinical trials that delivered fast results. Initially, The New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG), a committee advising the CMO and DHSC, carried out an assessment of potentially viable existing pharmaceuticals that could be repurposed. The group recommended prioritisation of potential therapeutics for formal evaluation in clinical trials based on key criteria (see table 1 below).

Table 1. NERVTAG recommendations on potential therapeutics

Consideration	Recommendation	Rationale
Inclusion criteria for consideration	Pharmaceutical agent is available or acquirable, with demonstrated efficacy against similar or comparable pathogens	Rapid trial initiation, efficacious agents identified will be readily available for wider deployment
Prioritisation of potential therapeutics for clinical trial	Greatest weighting for treatments showing efficacy in SARS-CoV-2 > SARS-CoV-1 > MERS-CoV	Maximise use of resources by focusing on agents hypothesised to have highest chance of efficacy
Prioritisation of potential therapeutics for clinical trial	Human > animal > in-vitro data	Maximise use of resources by focusing on agents hypothesised to have highest chance of efficacy
Outcome measure	Mortality > ICU admission > hospital admission > length of stay	Focus on biggest impact on reducing mortality and serious complications
Priority population for clinical trial	Mildly ill outpatients at high risk of complications	Reducing hospital admission in this group would have high impact in reducing demand on secondary care services.
Priority population for clinical trial	Moderately ill inpatients	Decreasing the rate of hospital complications (such as requirement for ventilation) and shortening length of stay would have a high impact on the ability for hospitals to manage demand
Encouraged trial characteristics	Randomisation, blinding, flexibility (regarding intervention arms and sample sizes), data minimisation and use of routinely collected data	Ensure high-quality results, minimise demand on healthcare and research staff
Encouraged trial characteristics	Explicitly consider need to include children and pregnant women where possible	Unknown if these are vulnerable groups at particular risk for severe disease or poor outcomes who would benefit from therapeutics. Need to establish pharmacokinetics or safety profiles which may be different to general population

To further support prioritisation of therapeutic candidates for clinical trials, the COVID-19 Therapeutic Advisory Panel (UK-CTAP) was then established which built on NERVTAG’s initial work. Potential pharmaceutical agents for treatment and prophylaxis of COVID-19 and, latterly, chronic disease commonly known as ‘long COVID’ were nominated through an open web portal. Prioritisation was based on several factors, including:^{[footnote 9]}

• scientific rationale (well defined modality of action relevant to pathophysiology of COVID-19 based on in vitro, pre-clinical and clinical data)
• pharmacokinetics and pharmacodynamics (to establish whether therapeutically relevant drug concentrations would be plausible and at what dose and regimen)
• safety and possible drug interactions
• availability and supply, including cost
• emerging evidence in human studies globally
• practicalities of giving the treatment (for example, intravenous drugs can be potentially useful but impractical at scale)

Recommendations were made to the CMO in England (at that time also CSA for DHSC) and trial investigators as to which drugs to trial, in which population and at what stage of the trials pipeline – and these were published online for transparency. This independent and centrally coordinated process minimised duplication of effort across the rapidly evolving clinical trial landscape.

Setting up clinical trials rapidly

Trial recruitment at speed and scale was crucial, and existing organisations rapidly pivoted to focus on COVID-19 in advance of the UK’s first wave.

ISARIC used co-developed pandemic preparedness plans and standardised trial protocols developed over the previous decade for MERS-CoV, avian influenza, Ebola virus and Zika virus, to rapidly facilitate recruitment for many trials.^{[footnote 10]}, ^{[footnote 11]}, ^{[footnote 12]}

The NIHR also built on established research processes such as the Urgent Public Health (UPH) process established in 2012 for the rapid set-up and delivery of research into unexpected and severe infections with the potential to cause widespread disease in the UK. Under the process, research studies designated highest priority were ‘UPH badged’, and eligible for prioritised support and resources.^{[footnote 13]} Such support included:

• prioritisation for recruitment within the NHS and clinical research networks (CRNs)
• favourable access to research delivery resources across the UK nations
• expedited regulatory review through Health Research Authority (HRA) and Medicines and Healthcare products Regulatory Agency (MHRA)

This process was activated in January 2020, and in February 2020 the CMO instructed NIHR to scale up the UPH process and lead on identification, funding and delivery of COVID-19 studies. The initial priority was testing existing, licenced drugs designed for other purposes (‘repurposed’) while waiting for COVID-19 specific therapies.

Within days of the UPH process being announced on 4 February, UK researchers submitted applications for research to be set up at hospitals, GP practices and non-NHS settings including schools, prisons and care homes. Over 1,500 submissions were reviewed and 101 studies recommended by an expert panel to the CMO in England and subsequently designated as priority studies. This resulted in full approvals being granted within an average of 8 days. The process meant that:

• competition for recruitment between trial platforms was minimised
• existing processes were sped up substantially
• access to national resources for trial recruitment and delivery was facilitated

Platform trials and the role of RECOVERY and other national trials

Priority national clinical platform trials to assess therapeutic candidates were set up in a range of patient cohorts. They were coordinated by NIHR and streamlined so that treatments could move through phase 1 to 3 trials rapidly. Trials included a number of patient groups:

1. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) study included hospitalised patients.^{[footnote 14]}
2. The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study, a repurposed platform trial used originally for patients with severe pneumonia in intensive care units (ICUs) pre-pandemic, included severely ill patients in ICUs.^{[footnote 15]}
3. The Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) study for repurposed oral medicines, and the Platform Adaptive trial of Novel antiviRals for eArly treatment of COVID-19 In the Community (PANORAMIC) study for novel oral antivirals, both included patients in the community.^{[footnote 16]}, ^{[footnote 17]}
4. The PROphylaxis for paTiEnts at risk of COVID-19 infecTion (PROTECT-V) study tested prophylactic interventions in vulnerable renal and immunocompromised patients.^{[footnote 18]}
5. The HElping Alleviate the Longer-term Consequences of COVID-19 (HEAL-COVID) study included discharged hospitalised patients recovering from COVID-19.^{[footnote 19]}
6. The Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways (STIMULATE ICP) study included patients with long COVID.^{[footnote 20]}

Clear support from senior leaders in the clinical system was essential – this included but was not limited to the CMOs and medical directors (see Appendix A: examples of public letters and statements from UK CMOs) as well as professional bodies such as the medical royal colleges. Without this clear guidance clinicians were under considerable pressure to prescribe untried treatments in the absence of proven treatments. It was not, however, uncontroversial.

The RECOVERY trial was one of the first and most successful UPH-badged studies, and was (and remains at time of writing) the world’s largest randomised controlled clinical trial for patients hospitalised with COVID-19. RECOVERY was designated a UPH study on 11 March 2020. It had received MHRA and HRA approval and recruited its first patient by 19 March 2020. It is an example of the constituent trials, but not the only successful one. RECOVERY built on trials initially set up in China using pre-prepared MERS-CoV protocols, before migrating to the UK when COVID-19 incidence decreased in China in order to ensure continued rapid recruitment. To ensure results were applicable to the national population, RECOVERY was deliberately inclusive, recruiting nearly 50,000 patients, ranging in age from less than 6 months to over 100 years old, one-third of whom were female, and one-sixth of whom were black, Asian or minority ethnic background. It had broad geographic spread across 195 hospital sites using in part established NIHR CRN infrastructure. Importantly it was a platform trial; drugs could enter and exit the trial on a rolling basis to allow multiple drugs to be tested simultaneously but with different start and stop points.

RECOVERY’s scale and breadth allowed for rapid, flexible and efficient testing of multiple treatments at the same time. Rolling analysis enabled rapid identification and reporting of results. The NHS, largely using existing NIHR CRN architecture, played an essential role, recruiting patients into RECOVERY as an integral part of clinical care including in non-academic centres not traditionally involved in delivering research of this type. To support rapid recruitment, biological and data collection requirements were kept to a minimum, reducing work for very stretched healthcare staff. Finally, data linkage of each recruited patient through their NHS record enabled progress to be tracked over time and across different healthcare facilities, enabling assessment of any long-term effects of the treatments on health outcomes.

The heavy emphasis on trials in the UK proved valuable. Within the first 100 days, 3 changes of practice were recommended. First, dexamethasone was recommended – contrary to understandable previous caution regarding the use of corticosteroids. Dexamethasone was the first drug to improve survival in COVID-19, reducing deaths by about one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]) and by one-fifth in other patients receiving oxygen only (rate ratio 0.80 [95% confidence interval 0.67 to 0.96]).^{[footnote 21]}, ^{[footnote 22]} This result was disseminated rapidly, and 4 hours after the first announcement of results UK CMOs wrote to all NHS hospitals recommending this become the standard of care (see Appendix A: examples of public letters and statements from UK CMOs).^{[footnote 23]} It is now recommended for patients with severe COVID-19 worldwide.^{[footnote 24]} Dexamethasone had the advantages of being well known to all clinicians, relatively safe, widely available and cheap, giving global applicability. There was, however, a risk calculation to be made between rapid dissemination and full peer review; this balance is explored in Chapter 3: research.

RECOVERY subsequently identified effective repurposed drugs including tocilizumab and sarilumab, immunomodulatory drugs used for rheumatoid arthritis which also reduced immune damage.

Equally importantly, RECOVERY ruled out repurposed drugs for which there was scientific and/or wider support but that showed no benefit such as hydroxychloroquine, lopinavir-ritonavir, aspirin, antibiotics and convalescent plasma – a treatment that had been used in over 100,000 patients before this finding was disseminated.^{[footnote 25]} These results were contrary to some prevailing expectations, emphasising the critical role that adequately large randomised control trials play in differentiating treatments hoped to work from those with rigorous evidence of effect. These highly powered trials meant that subset analysis identified several drugs that were effective in subpopulations, but had no or negative effect in others (such as heparin, which reduced mortality in moderately but not severely ill patients in ICU).

As the pandemic progressed, focus shifted from repurposed disease-modifying therapeutics (largely with impact on the immune system) to specific antiviral treatments and prophylaxis such as monoclonal antibodies against the virus and directly acting antiviral drugs. These were not available earlier in the pandemic.

New treatments under development by pharmaceutical companies since the start of the pandemic were approved in the second year of the pandemic after demonstrating safety and efficacy in clinical trials. These included:

• ronapreve, a novel monoclonal antibody combination product for use in the prevention and treatment of hospitalised patients
• sotrovimab, a monoclonal antibody for high-risk, non-hospitalised people and those with hospital-onset COVID-19

Collectively, these drugs reduced hospitalisations, had mortality advantage and reduced pressures on the NHS, although to date none with as large an effect as dexamethasone.

Antibody drugs against antigens had the advantage that they could be identified rapidly. They had the disadvantage that with each significant viral mutation it took time to identify whether the antibody still worked. Non-antibody antivirals against fundamental viral processes were much more likely to remain effective as the virus evolved.

Therapeutics deployment

Limited supply of drugs in a globally competitive supply situation meant that rapid decisions regarding procurement and stockpiling needed to be taken, often well ahead of efficacy results, to avoid the UK facing a market shortage when efficacy was proved. To address this, a multiagency collaboration called the ‘Rapid C-19 initiative’ was established between:

• NHS England and Improvement (NHSE/I)
• the National Institute for Health and Care Excellence (NICE)
• NIHR
• MHRA
• the Scottish Medicines Consortium
• All Wales Therapeutics and Toxicology Centre
• All Wales Medicines Strategy Group
• Department of Health in Northern Ireland
• DHSC’s new Therapeutics Taskforce (TTF)

The Rapid C-19 initiative sped up access to safe, efficacious treatments through horizon scanning to identify:

• credible or plausible therapeutic candidates (led by NIHR and NICE)
• health technology assessments (led by NICE)
• clinical policy development (led by NHSE/I)
• expedited regulatory processes (led by MHRA)
• simplified purchase and supply agreements followed by deployment at scale to the patient population (led by TTF and the NHS)

The TTF was established in April 2020 followed by a specific antiviral taskforce (ATF) one year later. As well as working with NIHR to support therapeutics trials, the TTF and ATF worked with industry and academia to identify and procure therapeutics and novel antivirals at pace and scale. They took strategic decisions on procurement and stockpiling of drugs at an early stage based on scientifically informed best guesses, working closely with the Deputy CMO for England on behalf of all the CMOs to ensure access to drugs for UK patients in the case of a successful trial outcome. Generally, sufficient confidence to put a repurposed drug into one of the key national clinical trials was taken as a strong enough signal that it should be purchased in bulk in advance at risk. This initial ‘no regrets policy’ has meant that where a NHS patient was eligible for treatment with a proven therapeutic, it was available.

As the pandemic progressed and vaccines were deployed, an advisory group supported by the NHS England Rapid-C19 team was constituted, which conducted evidence reviews, evaluating risk of poor outcomes using QCOVID© (a risk stratification tool) and ISARIC data to generate indicative risk groups, and triangulating these with a review of immunological evidence of the efficacy of vaccines in the context of primary disease or therapeutics that might compromise immune-competence. The work identified groups that were deemed to be at highest risk of hospitalisation and death, and who would be most likely to benefit from targeted treatment deployment.

Vaccines

How candidate vaccines were developed and deployed

Strengthening and speeding up existing processes

The development of vaccines for SARS-CoV-2 built on decades of global research and preparation, benefitting from previous work to develop prototype vaccines for SARS-CoV-1 and MERS-CoV and decades of research to develop mRNA vaccines, many of which were conceived as cancer vaccines. It was also supported by pre-existing protocols for rapid vaccine implementation in the face of a new global pandemic, and existing networks such as the UK Vaccine Network (UKVN) which was established in 2015 to address the lack of incentive for the pharmaceutical industry to develop vaccines for intermittent infectious disease outbreaks. Discovering, developing and approving a new vaccine has in recent history generally taken between 10 and 20 years. In developing a vaccine for SARS-CoV-2, there was an unprecedented universal mission focus on speeding up and expediting existing processes and creating agile alternatives in order to deliver a safe and efficacious vaccine to the population as soon as possible (Figure 1).

Figure 1: SARS-CoV-2 vaccine development timeline^{[footnote 26]}

Text for Figure 1: SARS-CoV-2 vaccine development timeline

Flow chart setting out the accelerated vaccine development process. Timeline is from 0 to 10 months plus.

At the start of the timeline, the first stage is design and exploratory preclinical studies.

Second stage is process development, preclinical and toxicology studies.

Third stage is clinical trial authorisation.

These 3 stages take place from 0 to 4 months approximately.

The next step of the process is starting overlapping clinical trials (phases 1, 2 and 3). Before phase 1 ends, phase 2 begins, and then phase 3. There is ongoing safety assessment throughout the clinical trials.

During phase 3, large-scale production and manufacturing of the vaccine begins at risk.

Throughout all trial phases is a rolling regulatory review.

There were important actions taken to speed up the process: the NIHR and UKRI rapid research call released in February 2020, for example, funded Oxford University to reorientate their adenovirus vector vaccine platform against the partially UKVN-funded MERS-CoV vaccine to develop a COVID-19 vaccine. Other developers used similar approaches to expedite development, using modified production processes from pre-existing vaccine candidates, or preclinical and toxicology data from related vaccines. mRNA platforms were initial frontrunners, building on 30 years of vaccine research that had resulted in mRNA vaccine candidates for influenza A, respiratory syncytial virus and cytomegalovirus, among others, but with no marketable products.

Use of this existing technology and learning cut research time and allowed mRNA vaccines to enter trials very quickly. Moderna, for example, started phase 1 trials in March 2020.^{[footnote 27]} Rather than running phase 1 to 3 trials sequentially, many developers ran phase 1 and 2 in parallel, such as Pfizer running phases 1 and 2 in May 2020. They also mass manufactured vaccine bulk substance ahead of efficacy results, substantially speeding up timelines, albeit at financial risk. Trials were targeted at high prevalence areas such as the USA, the UK, South Africa and Brazil, to accelerate recruitment. By autumn 2020, clinical trial data indicated that all 3 of the vaccines outlined above were highly effective at preventing symptomatic disease.

The UK, using NIHR CRN infrastructure, tested several vaccines developed in the private sector in other nations, including Novavax, Janssen, Valneva and Medicargo/GSK. Key institutions also supported an expedited vaccine development and deployment process. The National Institute for Biological Standards and Control (NIBSC) ensured quality of the final vaccine product through independent testing of each vaccine batch, and also developed reagents to support quick and reliable vaccine evaluation. NIBSC routinely conduct similar batch release testing for all licensed vaccines in the UK.

MHRA undertook a rolling review of data from clinical trials and manufacturing data as it became available to accelerate approval – the first time MHRA had instigated this process. By reviewing data from ongoing studies after initial analyses rather than as a package of all trial data at programme completion, blockages were identified and resolved earlier. MHRA authorised Pfizer, AstraZeneca and Moderna vaccines for emergency use on a temporary basis just under 8 months after trials started, and less than one year after the UK’s first case.

Mission-focused taskforces also helped speed up vaccine and drug development by setting direction for complex cross-agency working and bringing considerable external expertise into government. The Vaccine Taskforce (VTF), set up in March 2020, established formally in April and with a full-time leader appointed by late May, brought together experts from industry, academia and the civil service to secure an effective vaccine for use in the population by the end of 2020. It also worked with NIHR on the development and funding of post-authorisation trials to inform ongoing UK vaccine strategy (such as on boosters). The taskforce brought together government officials in DHSC and the Department of Business, Energy and Industrial Strategy alongside vaccinology and manufacturing experts drawn from industry and academia to provide expertise and credibility and to drive rapid decision-making. VTF’s due diligence team also supported rapid triage by recommending vaccines for clinical trial based on time to availability and plausible efficacy; with over 200 vaccine candidates in development, this was crucial.

The VTF also took a portfolio approach for research and development, manufacturing and procurement. Investment was made across multiple vaccine platforms. Contracting was centralised, and establishment of new flexible governance models sped up signing-off processes. The UK provided a relatively small commercial market for overseas companies. To strengthen its position, the VTF offered manufacturers troubleshooting across the development pathway, including linking with the UK’s considerable trials infrastructure to help companies prove efficacy, and with MHRA and HRA to prioritise and expedite regulatory approval processes.

JCVI and vaccine safety

Review and recommendation of novel vaccinations to UK health departments has been the responsibility of the Joint Committee on Vaccination and Immunisation (JCVI) since 1963. However, the need for expedient decision-making in a pandemic forced greater intensity. JCVI met twice weekly (compared with twice annually pre-pandemic), reviewing emerging evidence on a rolling basis to allow timely recommendations when appropriate. Weighting of JCVI’s usual priorities in decision-making also evolved, with vaccine supply, procurement and delivery capacity becoming higher priority considerations than usual, and programmatic cost lower priority than usual.

Issues of supply, procurement and delivery were more important than usual because of intense market competition globally and the need to make the UK market attractive. For the same reason, there was a need to pre-buy many vaccines, and so the question with programmatic cost was no longer whether to buy a vaccine but whether to use or discard a vaccine.

A guiding principle for JCVI was to maintain public confidence in a rapidly evolving environment through transparency while carefully considering any changes to advice in order to avoid confusion. This was particularly important for very rare side effects which are not ordinarily detected in vaccine trials and only observed and reported once the vaccine is being rolled out to the general population. During the first 2 days of vaccine rollout in the UK, more people had been vaccinated than in all clinical trials in the UK up to that point. When very rare complications of thrombosis and thrombocytopenia were reported after rollout of the Oxford/AstraZeneca vaccine first dose, JCVI initially recommended alternative vaccines for those under 30 years, later raising this limit to 40 years.^{[footnote 28]}

Vaccination in children and vaccination in pregnancy were both important questions that needed to be addressed in this pandemic. This is likely to be the case in a future pandemic as both groups are not ordinarily included in vaccine trials, though this depends on the pathogen in question. If, for example, a future pathogen impacted children more severely then the risk–benefit calculation would look very different.

Vaccination in pregnancy

JCVI also exercised caution when giving advice on issues with evolving evidence but updated such advice when further evidence came to light. In December 2020 at the start of vaccine rollout, for example, JCVI did not initially recommend vaccination for women who were pregnant or breastfeeding. At the time, although the available data did not indicate any safety concern or harm to pregnancy, JCVI noted that there was insufficient evidence to recommend routine use. As further data were obtained, guidance was updated, initially recommending consideration of use where the risk of exposures to SARS-CoV2 infection was high, or where women had underlying conditions that put them at very high risk of serious complications of COVID-19, before moving to recommending vaccination in all women in pregnancy.

Pregnant women were designated as a priority group in December 2021 following evidence of increased risk of complications, including maternal death and stillbirth, following COVID-19 infection in the third trimester.^{[footnote 29]}, ^{[footnote 30]}, ^{[footnote 31]} While this constituted an evidence-based approach to vaccine rollout in a potentially vulnerable group, the evolving messaging was misused by some groups to undermine vaccine confidence in pregnancy. With the benefit of data available later in the pandemic the decision to encourage vaccination in pregnancy would have come earlier, but that is with the benefit of hindsight.

Vaccination in children

Similarly, JCVI did not originally recommend vaccination of children, instead prioritising those most at highest risk from COVID. In December 2020 there were very limited data on adolescents, with no data on vaccination in younger children, and population data showing almost all children who were infected having asymptomatic infection or mild disease.

As the pandemic progressed, data accumulated on vaccine efficacy and safety, including incidence and severity of suspected adverse events, as well as on the incidence of rare complications following COVID-19 infection in children and young people (myocarditis, paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), long COVID). There was also growing evidence of the impact the measures taken to control COVID-19 had on children’s mental health and education.

JCVI made incremental recommendations in response to expand inclusion groups for vaccination to children aged over 12, and then offer (rather than recommend) the vaccine for 5 to 11 year olds. Decision-making regarding this group was much slower than for older age groups due to the finer benefit–risk balance as a result of the comparatively very low risks associated with COVID-19 infection in children compared with adults. On the question of vaccinating 12 to 15 year olds, as JCVI considered harms and benefits primarily from a health perspective, they asked UK CMOs to provide advice from a broader perspective (for example, considering impacts to education).^{[footnote 32]} The advice, supported by a range of expert input, found that taking into account both JCVI findings on marginal but positive health benefits alongside the likely benefits of reducing educational disruption and the consequent reduction in lifelong public health harm from educational disruption, vaccination in this group was recommended.

Vaccine scheduling

The National Immunisation Schedule Evaluation Consortium (NISEC) was formed in 2017 in response to a DHSC research call for vaccine evaluation to inform policy and decision-making for the national immunisation programme. The programme pivoted to COVID-19, establishing several national multicentre trials to evaluate emerging vaccines and inform choice of booster regimens (COV-Boost), mix and match regimes in case of vaccine shortages (Com-Cov), co-administration with seasonal influenza vaccination (ComFluCOV) and vaccination in pregnancy (Preg-CoV). Research design and priorities were codeveloped with DHSC, VTF, the UK Health Security Agency (UKHSA) and JCVI, with an emphasis on communication to ensure policy and guidance aligned in timing and content with emerging research.^{[footnote 33]} For example, JCVI and DHSC worked with COV-Boost chief investigators to agree the timing of key trial milestones so that timely data was available to inform JCVI decision-making regarding choice of vaccine candidates for the autumn 2021 booster campaign.

Vaccine deployment

The last stage of vaccine development – getting doses to the right people with equitable uptake – was critical, and depended on planning for the entire supply chain at the outset of the pandemic. Delivery of nearly 120 million vaccines across the UK within one year required advance procurement and provision of large amounts of vaccine cold storage, including minus 70°C freezers for mRNA vaccines and consumables (including hundreds of millions of needles, syringes and vials) at the start of the pandemic, to avoid deployment being slowed by a bottleneck caused by global shortages.

Workforce was equally important. Aided by an unprecedented effort from tens of thousands of NHS volunteer vaccinators and stewards, vaccination centres were set up across the UK in general practices, sports stadiums, places of worship, high street pharmacies and roaming mobile vaccination units (in England, for example, this was done with the aim that all residents were within 10 miles of a centre). The work was supported by Public Health England (PHE, subsequently UKHSA) and devolved equivalents and partners who distributed vaccines and components across the country and pre-assessed the UK’s infrastructure to ensure safe storage and supply.

UKHSA’s laboratory and population-based research informed vaccine research and development. Assessment of neutralising antibody titres and levels required for protection from infection were key early markers for evaluation of vaccine efficacy and, later, assessment of likely vaccine efficacy against emerging variants. The UKHSA laboratories worked closely with studies like COV-Boost and with vaccine manufacturers to facilitate much of their research. Close working between the UKHSA laboratories, DHSC and JCVI was important in aligning priorities and providing data at the right times.

UKHSA delivered the first real-world data on the effectiveness of the Pfizer vaccine from population data, further supported by its observational cohort SIREN study of over 40,000 healthcare workers, who were among the first to receive the vaccine. This provided among the first population evidence globally that the vaccine protected against infection, finding that healthcare workers were 70% (95% confidence interval 55% to 85%) less likely to develop asymptomatic and symptomatic disease after one dose of the vaccine, rising to 85% (95% confidence interval 74% to 96%) after the second dose.^{[footnote 34]} In the months that followed, UKHSA’s gathering of data on vaccine efficacy, safety in pregnancy and assessment of emerging variants and waning immunity informed governmental decisions on future vaccination policies and the wider global policy landscape.

Emerging considerations

Vaccine scheduling with limited supplies

The interval between first and second doses employed in phase 3 trials ranged from 3 to 4 weeks and was recommended for use by manufacturers and most regulators including MHRA. However, throughout December 2020, rising case numbers and the establishment of a new variant (Alpha) contributed to increased pressure to ensure as many people as possible received a first dose of vaccine rather than half as many receiving 2 doses, in order to save more lives overall.

On 30 December 2020, following MHRA agreement, the JCVI gave advice on extending the interval between the first and second dose from 3 to 4 weeks to up to 12 weeks, stating that the delivery of the first dose should initially be prioritised over the delivery of a second vaccine dose. The UK CMOs set out the rationale in a joint letter (see Appendix A: examples of public letters and statements from UK CMOs) explaining that the great majority of the initial protection from clinical disease came after the first dose of vaccine and that “in terms of protecting priority groups, a model where we can vaccinate twice the number of people in the next 2 to 3 months is […] preferable in public health terms than one where we vaccinate half the number but with only slightly greater protection”.^{[footnote 35]}

This deviation from trial protocol and manufacturers’ recommendations initially met with opposition from some professional groups as well as manufacturers. However, the decision was ultimately supported by surveillance and laboratory data proving higher effectiveness of the 12-week interval strategy compared with 3 to 4 weeks.^{[footnote 36]}, ^{[footnote 37]}, ^{[footnote 38]}, ^{[footnote 39]}

Prioritisation

The reality of a situation where novel vaccines are being developed during a global pandemic is that supplies will be limited initially, with increasing stock over time to meet demand. This is likely to be repeated in any subsequent pandemic. Prioritisation of specific population groups, therefore, was a necessary step in the planning process to ensure that those most at risk of severe consequences of COVID-19 had early access to vaccine.

JCVI reviewed UK epidemiological and clinical data, including:

• disease incidence, mortality and hospitalisation from COVID-19
• data on occupational exposure
• a review of inequalities associated with COVID-19
• mathematical modelling
• a review of evidence from different vaccination programmes

Based on this, it advised that the first priorities for the vaccination programme should be prevention of mortality, and protection of health and social care systems and staff with high occupational exposure and interaction with vulnerable patients, with secondary priorities including vaccination of those at increased risk of hospitalisation and at increased risk of exposure.^{[footnote 40]}, ^{[footnote 41]}, ^{[footnote 42]}, ^{[footnote 43]}, ^{[footnote 44]}, ^{[footnote 45]}, ^{[footnote 46]}, ^{[footnote 47]}

A programme combining clinical risk stratification, an age-based approach and prioritisation of health and social care workers was developed to optimise delivery and uptake by focusing on the highest risk groups (Table 2). Nine priority groups were identified and JCVI “estimated that taken together, these groups represent around 99% of preventable mortality from COVID-19”.^{[footnote 48]}

Table 2: summary of population groups and considerations for prioritisation^{[footnote 49]}

Population group	Scientific evidence	Ethics	Deliverability and implementation
Older age groups	Highest absolute risk of morbidity and mortality	Maximises benefit and reduces health inequalities	Age is almost universally recorded on NHS records, so easy to identify individuals; flexible delivery model to reduce inequalities in vaccine uptake
People with high-risk clinical conditions	Elevated relative risk; comorbidities increase with age; mediated/driven by other factors	Maximises benefit and reduces health inequalities	High-risk clinical conditions are well recorded on NHS records, so individuals are easy to identify; flexible delivery model to reduce inequalities in uptake
Health and social care workers	Elevated relative risk – mediated or driven by other factors not just occupation; vaccination of staff protects vulnerable patients	Contributes to individual benefit and population benefits: protect patients and ensure NHS and adult social care resilience	Health and social care workers can be identified through occupational health structures; established delivery model in occupational settings
Men	Elevated relative risk – mediated or driven by other factors, not just biological or genetic	Some benefit achieved by vaccinating older age groups and those with high-risk clinical conditions	Sex is almost universally recorded on NHS records, so men would be easy to identify
Black, Asian and minority ethnic groups	Elevated relative risk – mediated or driven by other factors, not just biological or genetic	Risks further increasing stigma; some benefit achieved by vaccinating health and social care workers	Ethnicity recording on NHS electronic systems is poor quality, so individuals would be difficult to identify; communications strategy and flexible delivery model to reduce inequalities in vaccine uptake

The JCVI prioritisation was supported by the COVID-19 Actuaries Response Group who explored the rationale for the priority order, demonstrating significant differences in vulnerability between the groups, with the number of vaccinations required to save one life increasing rapidly from vaccination of 20 care home residents to prevent one COVID-19 death, to 8,000 vaccinations of 50 to 55 year olds to prevent the same (table 3).^{[footnote 50]}

Table 3: overview of the number needed to vaccinate to prevent one death, per priority vaccine group^{[footnote 51]}

Vaccination group	Number of COVID-19 deaths as of 20 November 2020	Approximate population number (million)	Number needed to vaccinate to prevent one COVID death
Care home residents	22,800	0.5 million	20
80 years old or over	18,900	3.0 million	160
75 years old or over	6,300	2.2 million	350
70 years old or over	5,600	3.3 million	600
65 years old or over	3,100	3.3 million	1,000
60 years old or over	2,000	3.8 million	2,000
55 years old or over	900	4.4 million	4,000
50 years old or over	500	4.7 million	8,000
Everyone else	600	37.0 million	47,000

Note: some groups are not included because of limited data – for example, care home residents’ carers, frontline health and social care workers, the clinically extremely vulnerable, and 16 to 64 year olds with underlying health conditions.

Health and social care workers were also included. Although not highly vulnerable to severe disease, they had high exposures and interacted with a high number of those who were likely to die from COVID-19, so even a modest impact on transmission could have a significant impact on mortality in their patients. An evidence-based approach to prioritisation was essential and will be in future pandemics.

The prioritisation process then needed to be communicated, operationalised and above all accepted by the public and professionals. This took a lot of communication. The UK public in all 4 nations were extremely accepting of the need to prioritise, but rightly wanted to have a clear rationale laid out for why the prioritisation should be for others before their vulnerable family members and themselves. Once the logic was accepted the virtual queue based on risk was widely supported by the public, even when they were quite a long way down the priority list. Having national leaders visibly wait in (virtual) line based on this prioritisation was central to the perception and reality of fairness that clinical risk alone drove the priority.

An evolving virus, and population

Over the course of 2020 and 2021, the UK population had changed from an immunologically naïve population to a situation where the great majority had vaccine-derived and/or infection-derived immunity, especially against severe disease. Evidence generated from trials on an immunologically naïve population in 2020 was very challenging to extrapolate to this new population, with the challenge compounded by the emergence of multiple new variants. For example, the advent of the Omicron variant, with multiple spike protein mutations that partially or fully evaded monoclonal antibody targets, resulted in ronapreve being removed from clinical guidelines in the UK due to lack of efficacy. It also resulted in sotrovimab, one of the only remaining effective monoclonal antibodies, no longer being recommended by the US Food and Drug Administration due to similar concerns.^{[footnote 52]}

The loss of a large proportion of a previously effective drug class necessitated a change in focus of therapeutic strategy away from neutralising monoclonal antibodies to emerging small molecule directly acting antivirals, and a new ATF was established with the specific aim of securing 2 new effective antivirals. Antivirals were sensible to aim at as they are variant-agnostic and there were antivirals on the horizon. The UK government secured 5 million courses of oral antivirals to treat COVID-19 (paxlovid and molnupiravir), with over 80% of courses procured after the emergence of Omicron. Both antivirals have been shown to reduce the risk of hospitalisation and death significantly in trials. However, these trials had taken place in an unvaccinated population prior to the advent of Omicron.

To ensure comprehensive trials of novel antivirals in the real-world context of a heavily vaccinated population, drugs were entered into PANORAMIC, an interventional randomised controlled trial delivered through primary care for higher-risk patients in the community. Out of trial, targeted deployment of antivirals was reserved for patients at the very highest risk (such as severely immunocompromised, recent chemotherapy or radiotherapy). The first set of results from PANORAMIC came out in October 2022.

Antiviral resistance

Experience with HIV and hepatitis C virus, among other chronic infections, had highlighted the propensity of antiviral resistance to develop, particularly in immunosuppressed individuals on long-term treatment. While there is less evidence of resistance in acute viral infections (such as influenza), this was a plausible concern and so UKHSA expanded their antimicrobial surveillance programme to support and monitor appropriate use of therapies and mitigate antiviral resistance risk. Antiviral resistance risk needed to be balanced with the need to treat patients with available effective drugs, and it is important to have protocols to achieve this alongside antimicrobial surveillance. In the event of future viral evolution conferring resistance to directly acting drugs or vaccines, untargeted but broader acting pharmaceuticals (such as corticosteroids) have the potential to remain useful.

Vaccine equity

For vaccine programmes to work and be fair, uptake needs to be high across the population, geographically and in all ethnic and social groups. In common with vaccination programmes in other nations, COVID-19 vaccine uptake was lower, with higher rates of hesitancy, in more deprived areas and in minority ethnic groups which had also been disproportionately affected by COVID-19, potentially exacerbating existing health inequalities (see Chapter 2: disparities). It was important to tackle misinformation and disinformation swiftly, using trusted voices and communication channels to ensure all communities were getting scientifically accurate information (see Chapter 11: communications).

A number of barriers to uptake were identified,^{[footnote 53]}, ^{[footnote 54]} including:

• pre-existing mistrust in governments and institutions
• lack of information about the vaccine’s safety through trusted channels
• misinformation, including from country of origin in first generation migrants
• complex and changing UK guidance
• inaccessible communications, including language
• conflicting information from different information sources
• practical barriers such as the location of vaccine centres

Narrative syntheses have reported that reasons for vaccine hesitancy varied by ethnic group, with black groups more likely to cite mistrust of vaccines broadly and Pakistani or Bangladeshi groups more likely to cite concerns about possible side effects.^{[footnote 55]}

Work to address vaccine hesitancy and uptake in these communities was undertaken from the start of the vaccination programme but took time fully to develop. Strategies included a nationally funded Community Champions programme which supported local public health teams to work with communities and community engagement using ‘hyper local’ peer educators and trusted communicators. This helped amplify the voices of trusted local health and social care workers and religious representatives, remove practical barriers through provision of outreach teams in convenient places, including student unions and places of worship, and ensure communications were accessible, in a range of languages, locally appropriate and culturally sensitive.

While vaccine uptake increased across all minority groups over the course of 2021 and 2022, it has remained lower among certain communities, with booster uptake lowest among black African, black Caribbean and Pakistani adults, and in the most deprived populations.^{[footnote 56]}, ^{[footnote 57]} This reinforces the need for ongoing work to improve vaccine and health equities, but also for long-term engagement on health.

Reflections and advice for a future CMO or GCSA

Point 1

Speed of decision-making was crucial, particularly at the outset of the pandemic.

Decisions regarding research and procurement needed to be made early, and often ahead of complete information.

Point 2

An adequately powered trial with a faster result will prevent more deaths than an apparently perfect trial with later results.

Point 3

On the other hand, too many trials would have led to few or none reporting.

Some nations internationally experienced an explosion of trials, but with few getting to robust endpoints. Prioritisation of trial infrastructure based on realistic power calculations and patient flow and uptake were essential.

Point 4

The pressure to ‘just do something’ was intense on individual clinicians especially early in the pandemic.

High-profile senior support of research and pharmaceutical development (including CMOs) was needed for united and oriented cross-agency work and to ensure that the NHS prioritised enrolment of patients in trials.

Point 5

Existing research infrastructure (such as NIHR and MRC) and relationships (such as NHS and the academic community) were built on rather than setting up new organisations wherever possible.

This meant that the structures were functional and built on established relationships, resulting in rapid and more flexible work and, ultimately, better results.

Point 6

CMOs and GCSA are not responsible for procurement, but the rapid procurement of potentially useful drugs and vaccines at risk was essential and cannot wait for the final published trial results in an emergency.

Point 7

The model of the VTF, which integrated research and development, procurement and manufacturing, was important for rapid development and delivery of vaccines.

The VTF had a clear remit, single point accountability, brought in industry expertise and was empowered to make rapid decisions and deal directly with manufacturers.

Point 8

Balancing early dissemination of initial results against proper peer review of final results was never satisfactorily resolved in this fast-moving emergency.

The use of pre-prints, a novelty in the clinical (although not the academic) literature, was controversial. The dissemination of results just based on first reads of the data was even more so. UK CMOs only did this once, for dexamethasone. Their logic was that the drug was well known and relatively safe and the size of effect so large it was unlikely to unravel. It was, however, controversial at the time.

Point 9

Independent scientific and clinical advice was especially important for decision-making in areas where risk and benefit were less clear cut, or where there was more scientific uncertainty.

This included decisions regarding vaccination, especially of less vulnerable groups, particularly children, where JCVI had a critical role. The public understand the need for prioritisation of medical interventions such as drugs or vaccines based on clinical need. But they need to see the logic laid out, and fairness in execution.

Point 10

Vaccine uptake has proven to be the most important factor in reducing the impact of epidemic.

Uptake has, however, been particularly low in historically marginalised and ethnic minority communities which has widened inequalities, especially initially. Vaccination rates have also been influenced by deliberate disinformation and misinformation.

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