key: cord-0945789-413yt99x
authors: Sharpe, Hannah R; Gilbride, Ciaran; Allen, Elizabeth; Belij‐Rammerstorfer, Sandra; Bissett, Cameron; Ewer, Katie; Lambe, Teresa
title: The early landscape of COVID‐19 vaccine development in the UK and rest of the world
date: 2020-05-27
journal: Immunology
DOI: 10.1111/imm.13222
sha: 15d33b7b55df42227d2a8248dd9013593432f328
doc_id: 945789
cord_uid: 413yt99x

Since the first WHO notification on 31st December 2019, COVID‐19, the respiratory disease caused by the coronavirus SARS‐CoV‐2, has been responsible for over 4 million confirmed infections, and almost 300,000 deaths worldwide. The pandemic has led to over half of the world's population living under lockdown conditions. To allow normal life to resume, public health interventions will be needed to prevent further waves of infections as lockdown measures are lifted. As one of the most effective countermeasures against infectious diseases, an efficacious vaccine is considered crucial to containing the COVID‐19 pandemic. Following the publication of the genome sequence of SARS‐CoV‐2, vaccine development has accelerated at an unprecedented pace across the world. Here we review the different platforms employed to develop vaccines, the standard timelines of development and how they can be condensed in a pandemic situation. We focus on vaccine development in the UK and vaccines which have entered clinical trials around the world.

Live attenuated vaccines (LAV) are viruses that are rendered replication-incompetent through repeated passage in cell culture, and inactivated vaccines utilise whole pathogen which has typically been killed by exposure to chemicals (e.g. formaldehyde) or heat inactivation (33) . LAV are immunogenic and reproduce the breadth of the humoral and cellular immune protection that would be generated by live viral infection (32, 33) however inactivated vaccines are generally less immunogenic and require more than one dose or an additional adjuvant (34) .

Safety issues regarding the generation and subsequent attenuation of the virus, with potential for reactivation in vaccinated individuals, means LAV are not a tenable vaccine strategy for highly pathogenic viruses (33, 35) . This also prevents immunisation of individuals with weakened immune systems who are at further risk of illness if the pathogen reverts (36). From the perspective of vaccine distribution, LAV are generally kept refrigerated to preserve immunogenicity, which may be problematic in countries that cannot sustain cold chain distribution (34, 36) .

LAV for SARS-CoV-1 were tested in pre-clinical trials (37) . There is currently one company, Codagenix, proposing a computationally designed, lab-made SARS-CoV-2 'virus' that is immunogenic but not pathogenic (38) . SinoVac demonstrated safety and immunogenicity of an inactivated SARS-CoV-1 vaccine in a Phase 1 trial (39) , and have determined efficacy of a formalininactivated SARS-CoV-2 vaccine in rhesus macaques (40) (table 1) . Although this vaccine did not demonstrate any ADE-derived pathogenesis, previous whole virus SARS-CoV-1 vaccines trialled in mice induced eosinophil-derived immunopathology upon viral challenge (27), and Th2-driven histopathological changes in the lungs (31) .

Protein subunit vaccines include antigenic proteins thought to induce a protective immune response.

This vaccine type is produced in vitro and circumvents handling highly pathogenic live viruses (33, 41) . Subunit vaccines predominantly elicit a humoral antibody response, and most are administered with an adjuvant, which is a prerequisite to stimulate a strong immune response and generate a higher quality immune memory in humoral and cellular compartments. However, the inclusion of adjuvants can increase the reactogenicity and production costs, which are important considerations (41). Virus-like particles (VLP) are a type of subunit vaccine that present many copies of the relevant antigen in a 3D virus-like structure, and may be immunogenic enough to not require the inclusion of adjuvants (41). Subunit vaccines are an attractive vaccine technology for rapid vaccine development, and multiple   institutions worldwide are developing protein subunit-based vaccines (table 1) . They can be upscaled for mass production at good manufacturing practice (GMP) standards (42) , and distribution has less reliance on cold chain systems (34) . However, they can require bespoke manufacturing processes, which can increase cost, and may require specific mammalian cell expression and optimisation (18, 43) .

Similar to subunit vaccines, specific proteins from the target pathogen are chosen for their immunogenic epitopes, however these proteins are delivered as either plasmid DNA or RNA sequences (44, 45) . Upon vaccination, the host cell manufactures the pathogen protein, which is recognised by the immune system as foreign and generates an immune response (44 (34, 48) . Four DNA vaccines are available for animal use (46) , however there are currently none licensed for humans (49) .

There are several nucleic acid vaccines in development for COVID-19 prophylaxis (Table 1) . Nucleic acid vaccines are relatively cheap and rapid to manufacture, with the possibility to mass-produce large-scale GMP product (50) .

Recombinant viral-vectored vaccines utilise the host's innate immunity to generate self-adjuvanted immunogenicity, whilst eliciting a targeted immune response against genetically-encoded pathogen antigens (51) . The viral vector 'backbone' is constructed from a genetically-modified virus (52) , examples including adenoviruses, poxviruses, and Vesicular stomatitis virus (52, 53) . This vector typically has insertion sites for gene(s) of the target pathogen, which are expressed intracellularly in the host upon vaccination (54)

This article is protected by copyright. All rights reserved Important considerations for development of virus vectored vaccines is the generation of immunity towards the vector, which could hinder the antigen specific response upon a boost vaccination.

However reports from preclinical and clinical studies show sufficient protection can be elicited from a single dose (55, 56) .

Human adenoviruses (hAds) are a frequently used viral vector, however circulate at high frequency in most populations (57) , contributing towards demographically variable yet significant pre-existing immunity that can reduce vaccine efficacy (54). Vectors constructed from chimpanzee adenovirus (ChAd) were developed to elicit similar or superior immunogenicity as hAd vectors, whilst having significantly reduced seroprevalence and hence neutralising antibodies in most populations (28, 58) . 

Development of vaccines is a long process, taking at least 10 years per vaccine (66) . Most of the duration of vaccine development is determined by clinical trials, which are split into three phases between pre-clinical exploratory work and licensure of the vaccine (67):

 Phase I: First-in-human experiments on a small number of healthy volunteers, who have not been exposed to the pathogen. The trial focuses on safety and immunogenicity of the vaccine (67) .

This article is protected by copyright. All rights reserved  Phase II: Vaccines successful in phase I move into phase II trials. Phase II trials have a greater focus on the immunogenicity of the vaccine and expand the cohort across a wider breadth of the population, allowing for immune response to be analysed across age, gender, ethnicity, and other variables (67) . Efficacy may also be assessed at this stage, with controlled human microbial infection studies (CHMI) giving a useful early indication of potential efficacy for diseases where robust CHMI models are available (68) .

 Phase III: the efficacy of the vaccine is assessed across a larger population. Phase III studies enrol enough participants to ensure statistical power to assess if the immune response stimulated by the vaccine is sufficient to protect against disease. The clinical endpoint of phase III vaccine studies is often determined by reduction in case numbers or severity of disease in the cohort and requires an active outbreak (67) .

Vaccine trials are extremely expensive (17), representing a huge financial risk, and as such the vaccine timeline is extensive (66) . It is estimated to cost US$31-68 million to bring a candidate to the end of phase IIa trials (69) . Ethical acceleration of the trial can be achieved by performing Phase I/II and Phase II/III studies in parallel once sufficient data has been extracted from the preceding phase (70) . This can entail a larger risk from commercial investors and therefore requires philanthropic organisations such as Coalition for Epidemic Preparedness Innovations (CEPI) and others to fund the parallel phases to accelerate vaccine development through clinical trials at a rapid rate (70) .

There are a number of COVID-19 vaccines under clinical development at research institutes in the UK, at least three of which are at the pre-clinical stage, and one of which has progressed to clinical trial recruitment (Table 2) .

A self-amplifying RNA (saRNA) vaccine encoding SARS-CoV-2-S is under development at Imperial College, London. Previous saRNA vaccines against Influenza A haemagglutinin and Toxoplasma gondii NTPase-II have induced cellular and humoral immunogenicity in mice (71, 72) , and a first-inclass clinical trial using saRNA against hepatocellular carcinoma encoding the transcription factor

This article is protected by copyright. All rights reserved C/EBP- demonstrated acceptable safety and tolerability (73) . This COVID-19 vaccine is currently in pre-clinical testing, with a target clinical trial date set for Summer 2020 (74) .

Bristol University, with spin-out company Imophoron, is developing a SARS-CoV-2-S VLP vaccine with their adenovirus-based ADDomer© technology. Imophoron states that the ADDomer© VLP platform has many of the main benefits of VLP-based vaccines, including rapid development, selfadjuvant properties and no cold storage requirement (75). An ADDomer© VLP vaccine expressing Chikungunya E2 protein also proved immunogenic in pre-clinical trials (76) , although this platform

has not yet been tested in humans.

The University of Cambridge and DioSynVax are using a bioinformatic approach to design an optimal SARS-CoV-2 genetic sequence, which will be used to make a vaccine encoding SARS-CoV-2-S (77).

The University of Oxford COVID-19 vaccine has recently entered clinical trials in the UK (table 2) . The current planned phase II clinical trial will recruit volunteers between the ages of 55-70, age 70+, and children age 5-12 years to assess the vaccine across broader demographics. A phase III clinical Accepted Article trial is planned to recruit more than 10,000 volunteers over 18 years old to assess efficacy of the ChAdOx1 nCoV-19 vaccine (86).

In April, CEPI announced the number of COVID-19 vaccine candidates around the world had exceeded 100 (16) . Here we will focus on those candidates which have entered early clinical trials by

April 2020. Table 3 shows data on the protocols for each trial.

The Moderna and BioNTech platforms are messenger RNA (mRNA) molecules expressing SARS-CoV-2-S, contained within lipid nanoparticles to facilitate entry of mRNA into the host cells (87, 88) .

Once inside the host cell, the S protein will be expressed and induce antibody responses.The

Moderna vaccine was the first to progress to phase I clinical trials in humans (89).

The Moderna platform has been utilised in phase I clinical trials for several pandemic potential diseases, including MERS, Zika (clinicaltrials.gov NCT04064905) and pandemic influenza (87) .

Phase I data for a pandemic influenza vaccine focused on a cohort vaccinated with 25µg, 50µg or 100µg of vaccine. The vaccine had a good safety profile and showed seroconversion in volunteers who received the highest dose. Crucially, 87% volunteers who seroconverted developed neutralising antibodies. The platform did not however generate any measurable cell-mediated cytokine responses (87) .

The BioNTech platform has been used in Zika virus (ZIKV) vaccine development. Vaccination with a 30µg or 50µg dose in C57BL/6 mice and rhesus macaques respectively induced neutralising antibody titres against ZIKV, and protected challenged animals from detectable viremia (88) . This mRNA platform is also being used in phase I/II clinical trials for several cancer vaccines (90).

INO-4800, and the previous Inovio vaccine INO-4700, express either SARS-CoV-2-S or MERS-S respectively within an identical DNA vaccine vector (91). The vaccine is administered through Accepted Article intramuscular injection, followed by electroporation of the injection site. The need for electroporation may limit the ability of INO-4800 to be extended to the scales needed for a global pandemic and may be difficult to administer worldwide.

INO-4700 showed promising immunogenicity in a phase I clinical trial after multiple immunisations (92) . The trial administered three doses of vaccine, and was split across high, medium and low groups. Initial seroconversion peaked at 86% of the total cohort before falling slightly by the trial endpoint. Titres of neutralising antibodies showed similar pattern, peaking at 43% of the cohort 2 weeks after final vaccination, before being detected in only 3% of the cohort at the trial endpoint. 76% of the total cohort also showed an IFN-γ T-cell response against MERS-specific peptides (92) . 

to deliver a DNA vaccine expressing SARS-CoV-2-S into intestinal cells. The phase 1 trial of a COVID-19 vaccine will also be the first-in-man study of the bacTRL platform, so no previous immunological data is available (clinicaltrials.gov NCT04334980).

The Ad5 platform from CanSino Biologics demonstrated safety in Phase I/II trials for Ad5-EBOV (54), a vaccine against the Zaire strain of Ebolavirus. In addition, Ad5-EBOV induced humoral immune responses, with 100% seroconversion of vaccinees in a phase I trial. Volunteers also exhibited an IFN-γ T-cell response, significantly different from the placebo group, suggesting the induction of limited cell mediated immunity (54). This vaccine has subsequently been licenced for emergency use in China against Ebolavirus.

In the Phase I Ad5-EBOV trial, the study found participants with pre-existing Ad5 neutralising antibodies showed significantly lower humoral and cellular responses to the EBOV glycoprotein than participants that were seronegative against Ad5 (54).

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The Shenzhen Geno-Immune institute are utilising lentiviruses to transduce dendritic cells (DCs) and antigen presenting cells (APCs) to induce cytotoxic T-cell responses in patients who have developed COVID-19. Dendritic cells are a subset of APCs that can be modified to express and present antigens, and this property has been used in phase I trials with tumour-associated and neo-antigen cancer vaccines (93) . The trials will test both the efficacy of APCs as a vaccine alone (clinicaltrials.gov NCT04299724), and administration of modified DCs with donor cytotoxic T-cells as a combination therapeutic and vaccination (clinicaltrials.gov NCT04276896).

Sinovac has published pre-clinical data on efficacy of an inactivated SARS-CoV-2 vaccine in a macaque challenge model (40) . Rhesus macaques received 3 vaccine doses of either 3µg or 6µg at 1-week intervals. Titres of IgG and neutralising antibody after third vaccination were similar to those induced by natural infection in recovered patients. T-cell responses were not reported. Macaques were challenged 8 days after third vaccination and displayed a reduction in viral load compared to unvaccinated animals, encouragingly, there was no evidence of ADE or Th2-skewed immune responses in vaccinated animals (40) .

The COVID-19 pandemic has driven vaccine research and development into unprecedented territory.

Non-clinical suppression strategies involving contact tracing and social distancing have been employed globally to varying degrees (17) . There is growing evidence that these interventions have had considerable impact on 'flattening the curve' of the epidemic, thus reducing burden on overstretched healthcare systems, and allowing time for vaccine and antiviral development.

However, relaxing social distancing measures too soon may result in a second peak in infections (94) . The social, economic, and health effects of these measures on society will be fully realised over the coming months, although it is likely the cost of these strategies will be steep. Furthermore, healthcare facilities have been subjected to intense pressure and high demand, with supplies of personal protective equipment in short supply across the UK and internationally (95) . Together, these limitations put the lives of healthcare workers and patients at higher risk (96) . The length of natural protection post-exposure is currently unknown, and could result in regular circulation of SARS-CoV-2

if immunity is not long-lived (97) . The development of a safe and effective vaccine, therefore, is vital for mass protection of those most at risk from COVID-19-induced disease. This will reduce the number of hospitalised cases, subsequently relieving the burden on healthcare systems and will allow for relaxation of physical distancing interventions.

The ideal candidate COVID-19 vaccine would have good safety and immunogenicity profiles in all age groups and demographics including pregnant women and immunocompromised individuals, and would generate robust cellular and humoral immunity with a single vaccination, which could potentially be boosted for long-lasting memory durability (52, 63) . Single-shot efficacy was demonstrated in clinical trials during the latter half of the 2013-2016 Ebolavirus outbreak, where one vaccination of rVSV-ZEBOV conferred up to 100% protection for at least 84 days (55) . A chimpanzee adenovirus vectored vaccine (ChAd3 EBOZ GP) induced similar immunogenicity, also with a single dose, suggesting that multiple viral vector vaccines are effective at inducing high levels of immunity after a single dose (98) . Single-dose protective efficacy would offer fast protection to frontline healthcare workers and those in close contact with infected individuals, with additional booster vaccines to extend duration of immunogenicity if needed (97) . Public concerns surrounding vaccine safety may be heightened during the outbreak of an unknown pathogen and unclear scientific reporting. Vaccine hesitancy due to perceived risk is a globally observed phenomenon (99) , and care must be taken to ensure the public is aware that full safety and regulatory requirements of a new and rapidly developed vaccine against SARS CoV-2 have been completed with due care.

The ability to generate large quantities of GMP vaccine in a short duration of time is also essential.

The cost of producing COVID-19 vaccines for public use will be steep and exceed CEPI's $2 billion fundraising goal, which will establish GMP manufacturing sites, but not cover eventual vaccine manufacturing (17) . Global input will be necessary to fund and produce vaccines at multiple sites across the world, whilst ensuring fair and equitable distribution. It is hoped that more than one vaccine candidate undergoing current development and clinical testing will be suitable for mass vaccination in the coming year. In this manner, global need will hopefully be adequately addressed.

Unparalleled vaccine research and development is ongoing for the SARS CoV-2 epidemic. An efficacious and publicly available vaccine will significantly reduce the impact of the current and

This article is protected by copyright. All rights reserved possible future epidemic peaks, thus reducing burden on national healthcare systems. It is vital, however, that we continue to develop tenable vaccines that are both safe and immunogenic, can be manufactured at scale, and can be distributed to both economically stable countries and to lowerand middle-income countries ensuring equal access. 

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We would like to thank Professor Sarah Gilbert for help with reviewing, structure and content.

Teresa Lambe is named as an inventor on a patent application covering a SARS-CoV-2 (nCoV- 19) vaccine. The remaining authors declare no competing interests.

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This article is protected by copyright. All rights reserved