COVID-19 Vaccines – Have we got the capacity to develop a vaccine at rapid speed?

An interesting article by Nicole Lurie and others in the New England Journal of Medicine May 21, 2020 looks at the possibility of developing a COVID-19 vaccine at pandemic speed.

Clearly, there is a need to develop a vaccine against SARS-CoV-2 quickly.  This need comes at a time of explosion in basic scientific understanding within the areas of genomics and structural biology. 

Over the past decade, the scientific community and pharmaceutical companies have been asked to respond urgently to epidemics in producing a vaccine.  These have included H1N1 influenza, Ebola, Zika Virus and now SARS-CoV-2. 

The H1N1 influenza vaccine was developed relatively quickly.  This was largely because influenza vaccine technology was well developed and key regulators had previously decided that vaccines made using egg and cell-based platforms could be licensed under the rules and used for a strain change.  Although the monovalent H1N1 vaccine was not available before the pandemic peaked within the northern hemisphere, it was available soon afterwards as a stand-alone vaccine and was ultimately incorporated into commercially available seasonal influenza vaccines.

Unfortunately, vaccines for SARS, Ebola and Zika were not available so quickly and these programmes within the United States ended before vaccine development was complete. This resulted in manufacturers having financial losses and setting back other vaccine development programmes.

Development of the Ebola vaccine by the Public Health Agency of Canada was on hold between 2013 and 2016 when the Ebola outbreak began.  The United States government provided funding to accelerate the vaccine’s development, which was ultimately transferred to Merck, the pharmaceutical company.

Merck continued development even when the outbreak ended and stockpiles of the investigational vaccine were available for use in the recent outbreaks in the Democratic Republic of Congo.  The vaccine received conditional marketing authorisation from the European Medicines Authority and approval from the US Food and Drug Administration at the end of 2019 and in several African countries thereafter.  There is, however, the prospect that commercial markets will not sustain multiple vaccines for which relatively few doses may be needed in the future.

Reviewing the experience with H1N1 vaccine, there clearly exists a need for novel development and manufacturing platforms which can be readily adapted to new pathogens.  Vaccine and biotech companies have been investing heavily in these approaches and have been supported by the US government and other funders.  The National Institute of Allergy and Infectious Diseases in the United States led an initiative to support early development of platforms and test them against prototype pathogens from various viral families. 

The Coalition for Epidemic Preparedness Innovation, CEPI, an international non-governmental organisation funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission and eight countries including Australia, Belgium, Canada, Ethiopia,

Germany, Japan, Norway and the United Kingdom is supporting development of vaccines against five epidemic pathogens from the World Health Organisation priority list.  The CEPI aims to develop reserves of investigational vaccines for each pathogen after such vaccines have completed their phase 2A trials.  They expect that these vaccines will undergo clinical trials during further outbreaks. 

CEPI has also supported the development of platform technologies to prepare for Disease X – a newly emerging epidemic disease such as COVID-19.

The ideal platform would support development from viral sequencing to clinical trials in less than 16 weeks and be able to demonstrate a consistent immune response across pathogens and be suitable for large-scale manufacturing using a pathogen-agnostic platform.

Multiple platforms are under development and amongst those with the greatest potential for speed are DNA and RNA-based platforms followed by those for developing recombinant-subunit vaccines. 

RNA and DNA vaccines can be made quickly because they require no culture or fermentation.  Instead they use a synthetic process.  Developers and regulators have experience with these platforms for personal oncology vaccines and can therefore facilitate rapid testing and release.  There are no approved RNA vaccines to date, but RNA vaccines have entered clinical trials and regulators have experience in reviewing clinical trial applications and with those associated with the manufacturing of the vaccine.

Use of Next-Generation Sequencing and reverse genetics may also cut development time of more conventional vaccines during epidemics. 

However, even with these novel platforms, SARS-CoV-2 vaccine development poses many challenges.

  1. The virus spike protein – this is a promising immunogen for protection.  However, optimising antigen design is critical to ensuring optimal immune response.  There continues a debate as to what is the best approach – for example, whether to target the full-length protein or only the receptor-binding domain.

  1. Pre-clinical experience with vaccine preparation for SARS and the Middle East Respiratory Syndrome, MERS, raised concerns about exacerbating lung disease either directly or as a result of antibody-dependent enhancement.  Such an adverse reaction may be associated with a type 2 helper T-cell response. It is essential therefore that suitable animal models and rigorous safety monitoring in clinical trials is performed; it is still too early to define good animal models.

If adjuvants are required to generate a sufficient immune response or for dose sparing, then those triggering a Th1 response and demonstrating a high neutralising-antibody response are theoretically more likely to be protective and avoid the risk of immunopathology – however, data and careful regulatory review will be needed.

Although correlates of protection may be inferred from the experience with SARS and MERS vaccines, they have not yet been established.  As with all naturally acquired infection, the potential duration of immunity is unknown; similarly, whether a single dose of vaccine will confer immunity or not.

Vaccine development is a lengthy, expensive process and typically takes multiple candidates and many years to produce a licensed vaccine.  Because of the high cost and failure rate, vaccine developers usually follow a linear sequence of steps with multiple pauses for data analysis or manufacturing process checks.

Developing a vaccine quickly requires a new paradigm with a fast start and many steps executed in parallel before confirming a successful outcome of another step.  This results in an elevated financial risk.  For example, with platforms already in experience with humans, phase 1 clinical trials may be able to proceed in parallel with testing in animal models.

When China announced that a novel coronavirus had been identified as the cause of the Wuhan outbreak, CEPI contacted its partners that were developing the MERS vaccines or working on novel platforms.  With this potential for further financial support, they and others began vaccine development as soon as the first gene sequence was posted and development is proceeding quickly. 

Moderna’s mRNA-based SARS-CoV-2 candidate entered a phase 1 clinical trial in March 2020, less than 10 weeks after the first genetic sequence was released.  Regulatory clearance exists to start the phase 1 study in China with a non-replicating vector-based vaccine.

For some vaccine candidates, additional clinical trial material for phase 2 study is already being manufactured.  Proceeding quickly beyond phase 2 trials means manufacturing will also need to be scaled up to commercial levels before substantial safety and immunogenicity data are available.  Ensuring that there is manufacturing capacity will cost hundreds of millions of dollars. 

Furthermore, these novel platform technologies are mostly unlicensed and large-scale manufacturing has never been performed with them.  This will require facilities capable of producing large quantities of product with transference of technology and adaptation of manufacturing process – all without knowing if the vaccine candidate is viable.

It is essential that vaccines are also developed using tried and tested methods, even if this takes longer for them to enter clinical trials or to result in large numbers of doses.  It is far from certain whether the new platforms will be scalable or that existing capacity can produce sufficient quantities of vaccine fast enough. 

During a pandemic it is difficult to predict where and when outbreaks will occur and therefore where conducting clinical trials can happen. 

With the Ebola vaccine during the 2013 to 2016 outbreak, vaccines crowded the sites and burdened countries and their ethics and regulatory authorities. 

In a high mortality situation, populations may not accept randomised, controlled trials with placebo groups.  One possible way forward may be to test several vaccines simultaneously in an adaptive trial design using a single shared control group.  In this way more participants could receive an active vaccine.  This approach clearly has advantages but can be logistically and statistically complex and vaccine developers often avoid trials that may generate head-to-head comparative data.

No global entity exists which is responsible for financing or ordering vaccine manufacture.  Discussions with global stakeholders about organising and financing large-scale vaccine manufacturing, procurement and delivery are currently taking place. 

Finally, this pandemic will generate a simultaneous demand for vaccines around the world.  Once the vaccine is available, clinical and serological studies will be needed to confirm which populations remain at highest risk and criteria needs to be drawn up which will establish a fair global vaccine allocation system. 

It has been suggested that the pandemic may end abruptly before vaccines are ready.  Vaccine development should be continued with the most promising candidate so that it can be stockpiled and ready for trials and emergency use should an outbreak recur.

There exists a need for a global financing system that supports development and large-scale manufacturing and fair deployment.  This hopefully would protect private sector partners from financial harm and would be a critical component of future pandemic readiness. 

The London General Practice and The London Global Practice commends the CEPI and waits with anticipation for the development of a suitable vaccine for global use.  

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