Clinical Research and Development in PHEs (II): Vaccines

This webinar is part of our series on Preparedness Planning for Public Health Emergencies.

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Meeting Report

Professor Alan Boyd opened with a brief overview of the Faculty of Pharmaceutical Medicine (FPM) and welcomed everyone, with a special welcome to the FPM non-members.  

The FPM is a faculty of the Royal Colleges of Physicians (RCP) in the United Kingdom. The FPM is charged with setting standards for training and accrediting Pharmaceutical Physicians as well as establishing professional, deontological, and ethics guidance. The FPM’s Ethics and Practice Committee (EPC) focuses on the development of the FPM’s ethical and professional codes. The EPC forms a bridge between science and practice. Ensuring that patients have access to the medicines they need is at the centre of pharmaceutical medicine. 

Professor Alan Boyd’s first question asked: What are the major scientific challenges to developing a vaccine in a short period of time to respond to a PHE (i.e. COVID-19)? 

Professor Jeffrey Almond – stated that the short time of few months is a challenge for vaccine development as it normally takes approximately 10-15 years to develop a vaccine for established pathogens. Organisations’ culture systems, scale up, manufacturing, clinical trials, review processes by regulatory authorities and high costs are challenges even when there is more time. Pandemic planning has historically focused on Influenza, where there is a process to make a vaccine and scale manufacturing for a new strain. However, as this is a novel coronavirus, there is no defined process already in place. The immune response to provide protection against the infection is not well understood. Manufacturing itself can take several months to get up to the significant volumes required for worldwide vaccination distribution. Professor Almond explained that we need to be cautious with regards to positive news from companies, as developing a vaccine is not an easy process and not something that has ever been done previously in this timeframe.  

Professor Alan Boyd asked if we are promising too much to the public regarding a vaccine? Are we able to promise less? more? 

Professor David M. Salisbury cautioned that we need to be careful on the promises that we make. Currently there are over 100 vaccine development projects ongoing with at least 10 projects that are moving ahead to next stage development. It is tempting for researchers, developers to be overly positive about what they are developing. We do not know the speed of that progress toward a safe and effective vaccine that can be used. The first question might be: Who is promising? The companies and researchers tend to be promising about their vaccines. We have had information put into the public domain about mice (everybody in the vaccine world knows mice “lie”!), and on Phase I studies with very few participants. Are we promising too much? Are we not promising enough? 

There are potentially two ways out of the present Covid-19 pandemic: 1. The virus disappears. (not likely) 2. That we have a vaccine that protects us. (For how long a vaccine might protect us is a serious issue.) Claims made to date are based on very superficial data. We need to be careful to evaluate the bases upon which claims are made. Not all vaccines have the same mode of action and not all will have the same effect.  

We need to know 1. Is the recipient being protected? and 2. Is the recipient of the vaccine still infectious? We become vulnerable to the interpretation of claims being made by journalists who lack a scientific background. Politicians also should consider the wider issues of, not only having a safe and effective vaccine, but also when enough vaccine be available for all at risk populations to have received the required one or two doses. 

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Professor Alan Boyd stated that All medicines development is an experiment. Many experiments fail. He asked Dr. Human what he thought the political, societal, and funding challenges are to taking a rapid approach to vaccine development during a public health emergency? 

Dr Delon Human highlighted the tremendous complex effects on society:  

Political- There is risk in everything. Trying to explain the risks of a vaccine to parents is challenging. So implementing a potential Covid-19 vaccine is allanything but evident. 

For all governments on earth currently their highest priority is to address the pandemic. So the political race is on. The larger problem, however, is at the inter-governmental level. The WHO is also under stress now. Is the WHO in its current structure well set up for addressing such a highly politicized process? The high political pressure from member states makes it difficult for researchers to come to a rapid development programme for a vaccine. So perhaps another structure is needed to address pandemics that is connected to the WHO but independent politically. 

The need to innovate new vaccines, new diagnostics. The poor countries are usually the ones shouting for more access and the rich countries for more IP.  

Society– there is always is a tension between innovation and access across populations to new medicines. To find this balance is always a dilemma. During the time of the onset of the HIV epidemic, it was the patient organisations and representatives who were able to lobby for the access question to be addressed and they managed to drive prices of anti-viral therapies down, such that access was addressed as an issue. It is hoped that something similar will happen with Covid-19. The advantages of the digital age mean that more people can have access to the conversations, and this is promising for the discussion on access to medicines. 

Funding- Dr Human stated that CEPI has best practice in this area, with support from the Bill & Melinda Gates Foundation. Funding will become more of an issue when it comes to manufacturing. The ingenuity of the human mind and social solidarity are needed to ensure all are included in this conversation. 

Professor Alan Boyd asked if there will there be issues of who should access vaccines first? 

Dr Delon Human – In order to address access to the limited availability of a Covid-19 vaccine, it would be better if the current intergovernmental structure of organisations such as the WHO is separate from the normal political structure. 

Professor Jeffrey Almond – provided the example of Remdesivir® where it was announced today that the drug will be prioritised to the US population for next few months. We have seen in the last 48 hours that the political question is difficult. People will think that it is ‘their vaccine because it is made in their country and they have a right to it first’. The political dimensions will be difficult. It will make the PPE story look comfortable. Where are these smaller countries in the pecking order when it comes to accessing the vaccine supply? Equitable distribution must be arranged; however, it could be that priority will be given to the countries where the drug has been manufactured. This will make it difficult for developing countries to gain initial access to a Covid-19 vaccine. Important questions still to be addressed. 

Professor David M. Salisbury This is a difficult issue. Putting money into vaccine development and manufacturing will put them higher up  in receiving the vaccine. If you are a vaccine producer, there is a finite amount of vaccine you can produce each week. Does that go to a small number of your high paying clients? Or does that get split amongst all those who want it? The overarching mechanism for equitable access might not happen because it is too late to set up. The UK Government has promised that a vaccine will be available for the UK; however, it is not clear how equity comes into this as this means that the UK will be first. There are choices to be made between supplying vaccines to those that have contracts or supplying to those who are less privileged or cannot afford vaccines. In the 2009 pandemic, those countries that already had contracts in place got the vaccines first, the others who could afford it were next in line and, only at the end, those who depended on the generosity of others were able to access the vaccine. Professor Salisbury stated that the same may happen again, suggesting that if the vaccine could be split amongst all those who wanted it and be distributed in small parcels, it could be better than a sequential supply while protecting the most vulnerable. It might be best to look at countries with the highest transmission rates and the weakest healthcare systems first. The question arises whether these countries will have the infrastructure necessary to protect those at risk. This might not be in place in low income countries. 

Professor Alan Boyd asked if there are too many vaccines in development? 

Dr Jakob Cramer– CEPI is now supporting 9 vaccine developers. We have an open rolling call. Just this week we received over 60 submissions. There is a lot of heterogeneity in the applications. Some are early constructs. There is no way for those constructs to enter development in the next 9 or 12 months. Speed, scale, and access: these are the keywords in this call. Safety, efficacy, dosing schedule. the range/duration of immune response also need to be considered. It is already difficult to identify a suitable candidate. We try to spread the candidates and spread the risks of the vaccine candidates. Most vaccines are currently based on the spiked antigen. It would be good to include other antigens as well. We are supporting a ranging of platforms (the four types): spread this also across the globe. It is important to have a global development and a global availability of vaccines. While we do receive dozens of applications, there are only a few that have the actual experience needed to bring a candidate to success. You need to have enough pre-clinical, animal studies, clinical capacity, and more. You need to be able to get through development quickly. What is ultimately important is the manufacturing capacities of the developers. Even the smaller biotechs and the universities have partnered with companies (e.g. Oxford University with AstraZeneca). It is not just about identify a promising vaccine construct, but one also needs to partner it with a successful group to produce hundreds of millions of doses. 

CEPI has a budget of 1.4 billion dollars to develop vaccines. Contracts with CEPI can only be placed if the development is not located in one country. Normal development is 10 to 15 years. But we do not have that time. We are investing now at risk. This is taking a large vaccine. It only works if we have hundreds of millions of doses of an effective vaccine. 

Professor Alan Boyd then turned to questions from the audience, beginning with ‘How effective does a vaccine need to be?’ 

Professor Jeffrey Almond – stated that ideally one would like something that, not only prevents infection in the vaccine recipient, but also interrupts transmission. And then a vaccine that is produced in large doses and is widely available. Only then can one think about a return to normalcy. 

Professor Alan Boyd asked a posed by Karen Ma in the audience: How effective does a vaccine need to be? 

Professor David M. Salisbury –The vaccinated individual wants to know that they have 100% protection. If a vaccine has only an efficacy of 70% in the population. would we still be in lock down? What about the community? Each time we increase the proportion of the population that is vaccinated and the proportion that the vaccine works. If by the time we have sufficient vaccine, we are not hearing about the daily deaths, will there be reduced uptake by the public? If we have rushed a vaccine and we have compromised on safety, is this then acceptable? There is the question also of what proportion of the population needs to be vaccinated. The challenge on acceptability of a vaccine must not compromise on safety. There are many complicated interfaces between the acceptability of vaccine for those to receive it 

Professor Alan Boyd posed a second question from the audience: ‘Have we taken account of the possible genetic mutations of the virus in the development of a vaccine?’ 

Professor Jeffrey Almond – We do not see the same amount of antigenic variation in Covid-19 as we do with flu. I tend to the view that this will not display that level of variation. We need, however, to be constantly vigilant regarding new corona viruses. 

Professor Alan Boyd posed a third question from the audience: ‘If we administer the hundreds of thousands, millions, billions of vaccines worldwide, what is the risk/benefit at the population level and with whom will liability lie?’ 

Dr Delon Human – All risk and liability should not lie in the hands of one company. A system for the mitigation of risk and the sharing of liability will be needed. Here we need some form of inter-governmental cooperation to set the rules. In comparison with previous pandemics, data usage has become much more important. This can help us better measure the risk and reduce the risk. Developing the rules, however, takes a lot of time. Maybe Covid-19 can help promote partnerships in reducing the risk and liability. 

Dr Jakob Cramer- There are several aspects of risk-benefits for us to consider regarding funding. Early stage information on a vaccine candidate is important. Is this a promising candidate? Is there a platform for development already there? Is there clinical information? This are questions we consider when making an investment. 

Critical is that the regulatory authorities will have to make risk-benefits assessments based on the data submitted. We need a vaccine and manufacturing, but we also need a license from the regulatory authorities. We need to think of post-licensure commitments and data now. There is already a lot of discussion now by the WHO and country-level regulatory authorities. It is also important to think of regular safety assessments. There have been many discussions with WHO to define case-assessments. Dr Cramer concluded that it is also important to align and communicate well between regulatory authorities in different countries. 

Professor Alan Boyd asked: Do you think we could arrive at the level where one country / one regulatory agencies will do it for the world? 

Dr Jakob Cramer– stated that different agencies are talking to each other. The FDA has issued guidance that has generated discussion, including among other regulatory agencies. Presently we do not have a streamlined process across regulatory agencies. In the end trials will probably most likely follow the requirements of the most stringent regulators. 

Professor Alan Boyd asked a final question on how can we be better prepared for the next pandemic? 

Dr Jakob Cramer- stated that data sharing was critical. Also approaching 3 different regulatory agencies does not make sense and that the harmonisation of data, access and regulations is needed. 

Professor David M. Salisbury We must learn about developing rapidly moving and efficient tools that can respond to unexpected outbreaks of pathogens. 

Dr Jakob Cramer– We try to bring everyone around the table. It is not easy. There are things moving ahead on their own. We need to align, coordinate, collaborate. 

Professor Jeffrey Almond – Since Ebola we have seen the rise of new platforms being developed for vaccines to address different pathogens. Platforms are great but we also need to develop on to that for a given platform to be rapidly scaled up. RNA seems promising, perhaps more so than a general biological. He concluded that there is still more work to be done. 

Professor Alan Boyd thanked the panellists. We have had excellent discussions with exceptionally good questions from the audience. The next FPM Ethics & Practice Committee webinar in this series will be held on July 15th. We will then focus on paediatrics and public health emergencies. Thank you to the panellists and to the audience.