A COVID-19 vaccine—dare to dream

On 12 March 2020, the World Health Organization's (WHO) Director-General Tedros Adhanom Ghebreyesus declared a global pandemic of COVID-19, a disease caused by a novel coronavirus first identified in December 2019; patients in WuHan Province, China were presenting with atypical pneumonia and respiratory distress. The impetus of making such a statement reflected the emerging graphic of the international spread of the disease. Region by region, city by city, health departments around the world were reporting an escalating number of people presenting with acute respiratory infections and experiencing mounting pressure as they struggled to respond to the demands of this new public health threat.

The strategic effect of announcing a pandemic was designed to achieve more than stimulate individual countries to accelerate their efforts; the aim was to strike the right balance between protecting health, preventing economic and social disruption and respecting human rights (WHO, 2020). Learning from previous epidemics and sharing of resources, experience and developments in therapeutic possibilities to slow the virus became a critical element in the global crisis.

The universal goal endures as we head into winter 2020: stop transmission and prevent the spread of the virus in order to save lives. To do this requires a stringent approach to prevention and control measures that reach beyond individual territory borders and into a united investment into the ethereal sphere of vaccine development.

The context

The global and national restrictive measures in place to reduce the risk of transmission of COVID-19 and to prevent the excessive demand for secondary and specialist life support include closures of borders, schools and workplaces. There is little to no industry left unscathed by this pandemic anywhere in the world. Leisure, manufacturing, tourism, finance, education, technology, communication, politics and ironically, possibly healthcare least of all, have had established models of delivery and forecasting sabotaged. Whereas the global nature of our interdependency-in supply chain, international logistics of raw materials, goods and services and divergence typifying market growth-has traditionally been perceived as a strength, the global movement of people has arguably been the weakness enabling the reach of the virus at an unprecedented rate and breadth of reproduction (R₀) impacting the world economy (Maital and Barzani, 2020).

In the UK, the Government strategy on easing of restrictions and a return to a semblance of normal societal functioning is contingent on the availability of an effective vaccine. As well as enabling recovery of the wider economic domains, therapeutic and prophylactic development has two main objectives: preventing transmission of infection and reducing the associated burden of disease and mortality. The immediate and measurable outcome of the COVID-19 pandemic is loss of life and prolonged recovery in those who recover from the disease. The non-COVID-related mortality and lost quality life years due to lost opportunities for preventative healthcare interventions, such as timely access to cancer treatment and global resurgence of vaccine-preventable disease due to missed doses of childhood immunisations (LSHTM, 2020), must be considered within the context of the longer term impact of global authority response to pandemic SARS-CoV-2.

The challenges thus far

A necessarily slow, arduous and painstakingly detailed process is mandated for the development of vaccine material, and huge numbers of promising avenues of investigation fail to satisfy the prescribed stages of scrutiny to enable raw vaccine material or process to advance from ‘the bench to the bedside’ process (Hanney et al, 2020).

The process described below is carefully designed and regulated to provide a level of safety that reflects the gold-standard ambition of a vaccine that delivers life-long host protection without eliciting undue side effects. Not all vaccines can deliver this biosecurity; childhood measles vaccination, for example, requires a booster immunisation 18 months after the initial exposure. However, investigation during the phases of development enables this detail to become evident and allows a solution to be rigorously defined in the vaccination schedule. The levels effectively ensure a process of refinement; only when each standard is successfully passed should the next be explored. Hanney et al (2020) suggested that the entire process can take as long as 17 years; this immense commitment of resource highlights why seeking funding is a perpetual and embedded element of research study, particularly the higher-risk earlier stages of development (Table 1).

A traditional lack of interest in the usual vaccine development can be explained, in part, by a typical low market yield and low commercial value in addition to the high stake of early investment.

Literature prior to the pandemic highlighted learning from previous outbreaks of zoonotic disease (Alharbi et al, 2017), where the themes of study were focused on the high proportion of infected people dying as a result of progressive disease (Mubarak et al, 2019). The therapeutic view was perhaps drawn to reducing the impact of viral reproduction in those infected to reduce the pathogenesis of disease rather than arming the innate defence mechanism of the host to prevent transmission. These two features of therapeutic intervention have been at the forefront of the race to develop an effective vaccine against SARS-CoV-2, and prior learning has contributed to the earliest concept phases resulting in the current platform of potential vaccine availability.

Host-targeted therapies can be aimed at enhancement of innate immune clearance of SARS-CoV-2 or inhibition of inflammatory damage to the airway, reducing residual local damage and reducing the risk of secondary bacterial infections (Parks et al, 2020). The genome of SARS-CoV-2 encodes the multiple proteins that make up the initial interaction between the virus and the host. This contact and subsequent replication stimulates the cell-mediated response of the host immune system.

The SARS-CoV spike (S) protein on the surface of the coronet protrusions comprises two subunits and plays a key role in the induction of neutralising-antibody and T-cell responses and protective immunity during infection (Du et al, 2015). Building on earlier work, hypotheses can be generated as to the likely molecular target sites for SARS-CoV-2 vaccine development. In one study using macaque monkeys as the animal model, vaccine-elicited neutralising antibody titres correlated with protective efficacy, suggesting an immune correlate of protection satisfying the objectives of the pre-clinical phase of study (Yu et al, 2020).

The unprecedented demand for an accelerated response to this exceptional global emergency is testing ethical and clinical risk frameworks; yet, researchers are applying proof of concept of prior investigation to inform biochemical innovation. Hanney et al (2015; 2020) advocated the need for innovative practice to reduce time-lags in the development process. Their work advocated a matrix approach to empower synergistic and parallel arms of research and drug manufacture, delivered by multiple stakeholder agencies pooling and, therefore, increasing resources. In the interest of time-critical development, they encourage working ‘at risk'-a term that should not be assumed to be reflect a safety hazard, but is rather reflective of the financial uncertainties of targeted investment into possible solutions. The financial cost: benefit of facilitating access to greater resource essentially improves the efficiencies of the processes of achieving funding and ethical approval. Regulatory decision-making and, therefore, access to the next stage is enabled in preference to the conventional inhibitory features of requesting and queueing as due process of vaccine project management.

Host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa are required to expose the viral S2 spike protein for fusion to the host cell membrane and enable entry of the virus into the host cell. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity, and Belen-Apak et al (2020), while reflecting on the urgency of the SARS-CoV-2 pandemic, contested that their hypothesis should be factored into compressed phasing, thereby omitting phases I/II of the clinical product development process. In this instance, they advocated the clinical trial of a familiar and well-tolerated human therapeutic, unfractioned heparin in intensive care unit (ICU) and non-ICU hospitalised patients, relying on the risk–benefit judgement of the clinician to guide the intervention.

Exploiting the advantages of using a platform of initial scientific discovery to advance to further phased research is exemplified by Wang et al (2020). In their randomised controlled trial during the early weeks of the COVID-19 infection in China, remdesivir was evidenced to reduce the time taken to clinical improvement. This model was based on earlier proof of concept in vitro and in animal models of the inhibitory process of remdesivir on Middle East respiratory syndrome coronavirus, SARS-CoV-1 and SARS-CoV-2 replication (Wang et al, 2020).

Opportunities in vaccine development

The drive to produce a vaccine to stop SARS-CoV-2 transmission and control COVID-19 is uniquely framed due to the circumstances of the pandemic. The need to establish a means of quality-controlled mass production and the means of packaging to enable transport and administration to a global consumer is a critical element of the vaccine development process and is merged with phase III.

First, the demand for a SARS-CoV-2 vaccine is universal; the commercial market is suddenly limitless, and this dispels the usual lack of interest as a viable commercial entity. Whereas some developers such as AstraZeneca, GSK and Sanofi and Janssen are pursuing the development of a vaccine on a non profit basis, at least for the pandemic period, others view the resources and risk that they are assuming as justification for seeking a profit (Bingham, 2020). Further, the demand is urgent, unparalleled in focus, from government, pharmaceutical and health technology agencies, and the priority workstream is far beyond healthcare but of equal eminence across the political, economic and social landscape. The UK alone had committed to purchasing 60 million doses from established pharmaceutical manufacturers Sanofi and Glaxo Smith Kline (Sanofi, 2020), and as of June 2020, committed £84 million of Government investment for vaccine development.

Second, administrative infection control measures have impacted significantly on facility capability to start or continue programmes of study. The pandemic has reduced capacity in laboratories as a result of researcher restrictions on travel and logistical delivery of reagents and laboratory kit. There is a need, therefore, borne out of necessity, to seek opportunities to work in collaboration (Hanney et al, 2020), and progress is evident at collegiate, commercial and international tiers of the projects, including the example of UAE sponsoring China in one of the few WHO-listed vaccine candidates achieving phase III development (Chinese Clinical Trial Registry, 2020).

Much of the pre-clinical work and themes of focus are derived from the previous emergence and industry response to epidemics of SARS-COV-2 and MERS-CoV. Platforms of experimentation, data and learning exist, from which work contributing towards the wider concepts was developing in universities. Wrapp et al (2020) identified that the SARS-CoV-2 spike was 10–20 times more likely to bind to ACE2 on human cells than the spike from the SARS virus from 2002. Despite similarities in sequence and structure between the spikes of the two viruses, three different antibodies against the 2002 SARS virus could not successfully bind to the SARS-CoV-2 spike protein, suggesting that potential vaccine and antibody-based treatment strategies needed to be unique to the new virus.

The strategic innovation in vaccine development has been unprecedented; significant examples of the active removal of geographical and political barriers to participatory standardised methods of work exist. Globally, the WHO and the US Food and Drug Administration (FDA) have advocated an adaptive trial design, enabling the evaluation of multiple vaccine candidates in parallel against a single placebo group, as a pragmatic method to increase efficiency (Hodgson et al, 2020). In the UK, vaccine developers have had access to standardised research tools of accredited T-cell and neutralising antibody assays, in order to coordinate results from the multiple international clinical trials (Bingham, 2020). The UK established the Vaccine Taskforce-a dedicated, responsive private-sector team of scientific and industry experts embedded in the Government to drive forward the development of vaccines for the UK and internationally (Bingham, 2020).

Selecting viable vaccine candidates

Vaccine development was characterised by long lag times; applying for funding streams and narrating proposals for grants takes time, and resource and development are entirely dependent on achieving adequate investment. Some 90% of initial vaccine development projects fail (Hanney et al, 2020), and this process is equally as challenging: of 125 potential candidate COVID-19 vaccines approved at the pre-clinical stage, only six were within phase III clinical trial development by June 2020 (Hanney et al, 2020).

Stimulating immunity without disease progression (Clem, 2011) is the aim, but challenges in the science persist. Informed by the learning from the previous SARS and MERS epidemics, however, the evidence is that the required priming of T-cell and inherent memory that confers immunity is challenged by a distinct lack of cooperation between the B-cell and T-cell functions in some patients who test positive for the virus with the polymerase chain reaction (PCR) test.

Two candidates offered potential by June 2020 (WHO, 2020). Under phase III development by Sinovac and supported by Butantan Biomedical Research Institute in Brazil was an inactivated recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe SARS-CoV-2 strain. The published results from phase I/II in March 2020 of the initial 108 participants demonstrated proof of concept, as the vector-induced antibody response was effective and tolerated at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination (Zhu et al, 2020). However, phase II highlighted that the geometric titre level of neutralising antibodies was significantly lower than the binding antibody titres requiring the phase III protocol to give two doses of ‘Coronavac’. A further concern of this vaccine design when planning for an older target population is that antibody seroconversion rates were significantly lower in participants who had pre-existing high levels of antibodies against the vaccine's Ad5 vector and among older individuals (Zhu et al, 2020).

Considering that advanced age is a significant risk factor for poorer outcomes with COVID-19, it is entirely relevant to the objectives of vaccination that efficacy can be demonstrated in an older age group. The phase III randomised, placebo-controlled interventional study (NCT04456595) started in July involving 8800 participants, in which a cohort of older adults is included, is due to be completed (the last participant contact visit to collect data) in October 2021 (https://tinyurl.com/y39pue9u).

The ChAdOx1 nCoV-19 vaccine trial (NCT04400838), produced in a partnership between the University of Oxford's Jenner Institute and AstraZeneca, consists of an attenuated adenovirus capable of producing the spike (S) protein of SARS-CoV-2 (ISRCTN, 2020). Alharbi et al (2017) had described the coronavirus surface spike glycoprotein in receptor binding and membrane fusion enabling cell entry during infection as ‘an attractive vaccine antigen’ and demonstrated pre-clinical modelling that evidenced a single dose of ChAdOx1 MERS, a chimpanzee adenovirus-vectored vaccine that encodes the spike protein of the MERS-CoV, protected non-human primates against MERS-CoV-induced disease. Allowing for the formation of endogenous antibodies against the spike-specific proteins results in protection against SARS-CoV-2 and subsequent infection (El-Aziz and Stockand, 2020).

Phase I/II data suggested effective rapid antibody and T-cell response against SARS-CoV-2. During the randomised controlled trial of this phase between 23 April 2020 and 21 May 2020, 1077 volunteers aged between 18 and 55 years received the vaccine ChAdOx1 nCoV-19 or a placebo MenACWY vaccine; a small subset of 10 people received two doses of the vaccine. There were no serious adverse health events related to ChAdOx1 nCoV-19, and 100% of the participants' blood neutralised activity against the coronavirus. However, two doses may be required; a booster is required on day 28 (El-Aziz and Stockand, 2020).

Phase III of this trial is to confirm that the vaccine can effectively protect against SARS-CoV-2 infection across a wider spectrum of population. The time lag of the traditional process of vaccine development means there is a lower community prevalence of disease and, therefore, opportunity for exposure at the point on the epidemiological curve when a vaccinated cohort is ready to be challenged (Tsang et al, 2020). Promising work at the earlier trial process was abandoned due to a lack of subjects as a result of an improved situation in China (Wang et al, 2020). Many of the phase III trials underway are proving truly international with recruitment of thousands of subjects in countries such as Brazil, China and the US, where sustained community transmission and in vivo exposure to the virus is likely, giving confidence to the longer term measures of vaccine efficacy.

Main COVID-19 vaccine contenders

Phase III efficacy clinical trials of two leading vaccine candidates-Oxford AstraZeneca's adenovirus-vectored vaccine and Novavax's protein adjuvant vaccine (NCT04368988)-are well underway in the UK, with first phase III efficacy data due by the end of 2020 (Bingham, 2020). Initial results on 9 November 2020 from a third candidate, the BioNTech/Pfizer with Imperial mRNA vaccine trial (NCT04368728) using either an antigenic component of the SARS-CoV-2 prefusion spike glycoprotein or a trimerised SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (Pfizer, 2020), demonstrated 90% efficacy in preventing symptomatic COVID-19 in late-stage human trials (Head, 2020).

The evidence from the Oxford project demonstrated early potential: a single dose of ChAdOx1 nCoV-19 evoked an increase in spike-specific antibodies by day 28 and neutralising antibody in 10 participants after a booster dose in phase I/II (Folegatti et al, 2020). The initial sample size of 10 people meant the confidence interval of achieving this outcome was necessarily wide, and although a correlate of protection had not been defined for COVID-19, high levels of neutralising antibodies were shown in recovering COVID-19-positive patients. The evidence of a rapid induction of both humoral and cellular immune responses against SARS-CoV-2, with increased responses of neutralising antibodies after a second dose, was relevant on multiple grounds. First, achieving this level in animal studies had been shown to confer protection against COVID-19, and second, the correlation of neutralisation assays with IgG quantitation highlighted potential for development of a reliable neutralising antibody test that could indicate a longer term immunity, with latent implications for therapeutic use of convalescent plasma (Salazar et al, 2020).

Interim efficacy data published on 24 November 2020 indicated high levels of effectiveness against severe incidences of the disease, including an efficacy result of 70%-with the potential for up to 90% efficacy depending on dosage and regimen (GAVI, 2020). This has significance for the most vulnerable cohorts of people in societies, as by minimising the impact of COVID-19 in these groups may reduce demand for secondary and tertiary care. Monitored over the forthcoming year, the primary outcome measure of effectiveness for this study will be the number of people who proceed to develop symptoms and virologically confirmed (PCR positive) COVID-19 (Clinical Trials Register, 2020). Secondary outcome measures include the number of people who proceed to develop symptoms and virologically confirmed (PCR positive) cases of COVID-19 in the ChAdOx1-vaccinated arm versus the control and how many of these people experience adverse events, disease, hospitalisation and death associated with COVID-19.

Measures of seroprevalence and blood titre antibodies to SARS-CoV-2 proteins will inform future understanding of the effectiveness of vaccination against COVID-19 and SARS-CoV-2 transmission measured by whether sustained protection due to an enhanced immune response is evident. Although people with immune memory for SARS-CoV-1 mount cross-reactive responses to SARS-CoV-2, there is no evidence that this is sustained against an SARS-CoV-2 antibody response (Altmann and Boyton, 2020). Previous studies have asserted that IgM and IgG antibodies to coronaviruses, including SARS-CoV-2, wane with time (European Centre for Disease Prevention and Control, 2020), and understanding the likely duration of protection in an individual and population is inherent to establish the financial and public health value of the efficacy of any vaccine.

What happens now?

Various delivery frameworks are being considered in terms of how the vaccines should be prioritised. However, there is sound argument for having multiple vaccines available; diverse platforms and technologies can offer different strengths and be relevant in distinct epidemiological contexts (Hodgson et al, 2020). Further, neither one country nor supplier can hope to deliver against the global need, so multiple vaccines will be required (Bingham, 2020). Scaling up of manufacturing capability must be a priority to ensure availability of vaccine to those who need it; billions of doses will be required to effectively ensure population-level protection achieved from community herd immunity. The stability of the vaccines across transportation and temperature gradients varies, and choice of vaccine may well be dictated to by the logistic capability of a country or region. Various methods of administration may need to be developed for different target populations, and their peculiar immunogenic requirements, such as a nasal spray for children (Mubarak et al, 2019) or an adjuvanted option for those with a poorer innate response, much as the annual flu vaccine confers for the over 65 age group (Wagner and Weinberger, 2020).

Should late-stage clinical trials prove successful, pharmaceutical companies are priming themselves for the mass production and distribution role they will play. The availability of a vaccine depends on the success of the trial data that can evidence the vaccines' efficacy against exposure to sufficient rates of infection. The primary endpoint is to show that any one of the COVID-19 vaccines can protect against SARS-CoV-2 infection and reduce symptom burden in those infected (Bingham, 2020). Early indications are promising (Bingham, 2020; GAVI, 2020; Head, 2020; Pfizer, 2020;), although Hodgson et al (2020) noted that the most important efficacy endpoint-protection against severe disease and death-is difficult to assess in phase III clinical trials.

Prospective studies of vaccine effectiveness in real-world scenarios post-licensure are routinely needed (Hodgson et al, 2020), and it is imperative for public confidence in the principles of vaccination that well-structured, robust follow-up studies at the individual and cohort level are embedded in the phase IV period to ensure ongoing critique and learning of vaccine safety and optimum approaches to scheduling and administration.

The scale of demand means that the global community will need to mobilise all stakeholders to enable access. Thus far, the UK government has committed £548 million (Bingham, 2020). to the COVID-19 Vaccines Global Access Facility (COVAX), providing access to vaccines for the UK population and for lower income countries (University of Oxford, 2020). The nature of the pandemic means no country is safe from further outbreaks nor evolving pathogens unless all global players have equitable access to the security provided by effective population-level vaccination. Global collaboration and standardised approaches for assessing different efficacy endpoints will continue to be important to allow meaningful comparison and ensure that the most effective candidates are deployed (Bingham, 2020; Hodgson et al, 2020) and production up-scaled. To protect the UK NHS, the global community must be protected.

The future

The availability of a regulated and approved vaccine may not become a reality for most until late 2021; the vaccine efficacy may be limited to reducing morbidity and mortality in an at risk population and as a first generation in likely to be imperfect (Bingham, 2020). The viability of a COVID vaccine should be heralded, however, as a first step towards future therapeutic control measures in reducing viral replication and transmissibility of infection.

The collaborative work achieved to date and which will be conduted over the next few months will strengthen the global resilience and establish systems of information sharing and government response to enable informed, judicious and timely responsiveness to future global public health threats.

Interim and ad infinitum, successful control of outbreaks requires a package of evidence-based, complementary measures that apply effective infection prevention and control principles of droplet, contact and environmental hygiene, thereby reducing reservoirs and transmission of infectious matter. Avoiding face-to-face exposure with infected people requires a reset of the values that promote intolerance of absence due to acute illness. Ensuring that people, symptomatic with viral respiratory infections are supported to self-isolate from their communities for the duration of their symptoms, must become an embedded societal behaviour that will complement any programme of vaccination and contribute to saving lives.

KEY POINTS

• Development of any therapeutic options including vaccines against an emerging infectious disease is challenging due to the risk of resource investment versus perceived benefit
• The global interest in seeking a reliable and accessible COVID-19 vaccine to reduce morbidity and reduce demand for specialist healthcare is a critical factor in the speed and success of collaborative working to achieve this shared goal
• A successful COVID-19 vaccination programme is likely to require multiple versions with various methods of storage and administration to achieve the global herd immunity to impact on the prevalence of disease
• Vaccination when available, will be a significant adjunct in the package of measures necessary to prevent and control infectious disease

CPD REFLECTIVE QUESTIONS

• What has been a common site of interest for vaccine development against COVID-19?
• What, if any, do you consider are the risks in an accelerated pathway to support vaccine development?
• How do you feel the availability of a vaccine to you as a healthcare worker and to your most vulnerable patient cohorts will impact on your role and function?