As we look back on the Congress in Europe and forward to future events, a conversation with Dr Andrew Vaillant of Replicor links our event in Barcelona to the World Vaccine and Immunotherapy Congress in San Diego. As Chief Scientific Officer with 20 years’ experience, he has pioneered Replicor’s nucleic acid polymer (NAP) technology. With a focus on hepatitis B (HBV), his insight into therapeutic development is particularly interesting.
Unique challenges for HBV
We asked Dr Vaillant about the considerations that are required for HBV therapies, and he outlined several “unique challenges” for us. Firstly, the “production of a very large excess of non-infectious subviral particles (HBsAg)” hinders the immune response to HBV. Therefore, the processes involved in vaccine responses are also affected. A successful approach must “occur with the clearance of these particles”. The next challenge is that HBV “exists as a population of thousands of quasispecies all with varying immunoreactivities” as well as “immune escape potential”. Thus, vaccine candidates must “focus on engendering multiple different HBsAg-reactive T-cell species”.
As Replicor will be presenting at the World Vaccine and Immunotherapy Congress later this month, we asked for a sneak preview of what that might involve. Dr Vaillant graciously gave us an insight! He indicated that we can expected to learn more about “how the industry is faring in achieving” therapy milestones. On top of this, we will hear updates from Replicor’s access programme for REP 2139-Mg in “patients with chronic hepatitis B and D infection with very advanced liver disease”.
REP 2139-Mg may have caught your attention, and we heard it is “unique and industry-leading” so we wanted to find out why. It’s Replicor’s “lead drug in development for the treatment of chronic HBV and HDV infection”. It is unique in its ability to “directly” target non-infectious subviral particles.
“When combined with immunotherapy, REP 2139-Mg is achieving high rates of HBsAg loss and functional cure of both HBV and HDV infection. These are outcomes not achievable with currently approved therapies or with any other technologies currently in development.”
A wider lens
After we had asked Dr Vaillant to explain some of the finer points of Replicor’s work we took a broader approach. We asked about challenges that therapeutic developers are facing, and how they can be overcome. Dr Vaillant recognises that although Replicor is “not directly focused” on an HBV vaccine, a “properly designed therapeutic vaccine” would play an important role in “achieving functional cure of HBV”.
“With its unique platform of nucleic acid polymers (NAPs) such as REP 2139-Mg, Replicor is in a unique position to remove the immunoinhibitory HBsAg from patients to potentiate a vaccine response.”
In collaboration with vaccine companies, Replicor is pursuing suitable candidates to work “in combination” with REP 2139-Mg for “high rates of functional cure”. Technology evidently plays a huge role in Replicor’s work, but interestingly Dr Vaillant believes “all the technology needed is in place” already.
“We are focused on educating the field about how to use this technology to develop appropriately broadly HBsAg specific vaccines essential for functional cure of HBV.”
Disruptions and distractions
Our final question was on the issue of COVID-19, which has influenced the work of many of our speakers, whether direct or indirect. For Dr Vaillant, the pandemic “has taken the focus away from many diseases which also take millions of lives each year”.
“Chronic HBV infection is a disease which affects more than 300 million people worldwide and kills more than 1 million people each year. This death rate is rising due to the important and unmet medical need in this disease.”
Looking forward, Dr Vaillant hopes that “appropriate attention” will return to “other infectious diseases” like HBV and HDV, to “allow faster progress in the field”.
We are very grateful that Dr Vaillant took the time to answer some of our questions and to give us a preview of Replicor’s presentations at the World Vaccine and Immunotherapy Congress in November. We look forward to hearing more then and hope you will join us!
In a study published in JAMA Oncology in November 2022, researchers from America and Europe collaborated to demonstrate “clinically meaningful and statistically significant extension of survival” for patients with glioblastoma. The results are described as “astonishing” by Professor Keyoumars Ashkan, of King’s College Hospital in London. The team aim to “offer fresh hope to patients battling with glioblastoma”.
A deadly threat
The Brain Tumour Charitydescribes glioblastoma as the “most common high grade primary brain tumour in adults”. They are grade 4 brain tumours that are fast growing and likely to spread, and often return despite treatment. Brain Tumour Research suggests that they “almost never spread outside of the brain, spine, or central nervous system to other parts of the body”. They are also “complex”, making them harder to treat.
“The average survival time is devastatingly short.”
However, some patients survive longer than a year or up to 5 years, and the reasons for this are unknown. Current treatment options include surgery, radiotherapy, and chemotherapy. Unfortunately, the reported recurrence rate is nearly 100% and the study describes “dismal patient survival”.
A “fresh hope”
The study objective was to investigate whether adding the autologous tumour lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) results in extended survival among patients. It was a phase III, prospective, externally controlled nonrandomised trial that compared “overall survival” (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) with “contemporaneous matched external control patients treated with SOC.”
Conducted at 94 sites in 4 countries, the trial took place between August 2007 and November 2015, with data analysis in 2020/2021. 331 patients between the ages of 18 and 70 years were enrolled. Following surgery and a collection of tumour tissue for the vaccine manufacturing, patients received the vaccine or a placebo on days 0, 10, and 20, and then in months 2, 4, 8, 12, 18, 24, and 30 as well as “monthly temozolomide as SOC”.
“Each DCVax-L dose comprised 2.5 million DCs injected intradermally in the upper arm, alternating arms between treatment visits”.
The data suggest a “20% relative reduction in risk of death at any point in time for patients with nGBM” who are receiving the vaccine, and this benefit “increased over time”. Furthermore, for rGBM a 42% relative reduction is risk was indicated, with the benefit once again continuing over time.
Delivering the vaccine
Professor Ashkan describes the vaccine as a “personalised solution, working with the patient’s immune system, which is the most intelligent system known to man”. Although the vaccine is not yet available to patients on the NHS, the US company that manufactures it, Northwest Biotherapeutics, intends to seek approval.
Dr Karen Noble is Brain Tumour Research’s director of research, policy, and innovation. She states that this is the “first emerging therapy proven effective in treating glioblastoma since temozolomide chemotherapy in 2005”.
“What the brain tumour community hopes is for it to become affordable, possibly becoming standard of care – so available on the NHS.”
For Dr Henry Stennett of Cancer Research UK, this is “particularly exciting” because it can “improve outcomes for people who don’t usually respond well to therapy.” Although “stringent regulatory” steps need to be taken, it is a “big step forward”.
We expect to hear more about other updates in developing a glioblastoma therapeutic vaccine at the World Vaccine and Immunotherapy Congress in San Diego later this month. To join us there, get your tickets now.
While we were in Barcelona this year for the World Vaccine Congress 2022 we had the exciting opportunity to meet Dr Erin Spiegel, Vice President of Clinical and Regulatory affairs at PharmaJet. We have previously encountered PharmaJet’s technology in efforts against Polio, so it was fantastic to learn a bit more about the potential it offers. Dr Spiegel’s session at the Congress explored some of the challenges (and solutions) associated with nucleic acid vaccine delivery. We are grateful that she was able to make time to speak to us!
We began by asking Dr Spiegel a little bit about herself and PharmaJet for anyone who might not know what they are working on. As VP of Clinical and Regulatory affairs she brings a wealth of scientific and regulatory experience to the role. She told us that PharmaJet’s needle-free devices are “used pretty widely” but are most effective for “nucleic acid based vaccines”.
Needle-free technology sounds like an exciting prospect, and we asked Dr Spiegel about its potential applications. As a “geneticist by training” she is most excited about the “impact” that it can have on “DNA based vaccines in particular”. She tells us that “historically, DNA based vaccines and therapeutics, and gene therapies even have needed a vehicle or delivery device system”. However, PharmaJet is hoping to sidestep this, avoiding the need for electricity, for example. Furthermore, handheld devices can be used in more “remote locations” for a “much bigger” reach.
Addressing vaccine hesitancy
Another potential benefit to needle-free technology is the potential to address genuine vaccine fears. These contribute to vaccine hesitancy. For Dr Spiegel, the “intradermal platform” creates a “basically pain free” process. On top of this, it provides a work around the fear of needles, leaving “not a lot to be afraid of”. Finally, the “small handheld device” is unthreatening, and will have benefits for vaccinating children in particular.
One of the most pressing challenges that faces the whole vaccine industry is sustainability. As innovation is clearly part of the process for PharmaJet, we wanted to learn how this factors in. Dr Spiegel told us that they consider themselves to be operating in a “pretty sustainable” fashion. Working in two different countries, or continents even, they have established “high throughput manufacturing” of the systems. The injectors themselves are “reusable through 20,000 injections”. This is far better than single-use solutions!
For a company like PharmaJet, things are moving quickly, and as many of us have recently become aware, the vaccine space is responding to frequently developing scientific knowledge with amazing technology. We asked Dr Spiegel what recent advances have shaped her work. She identifies advances in both DNA and RNA based technologies. As we saw in COVID, the RNA is moving quickly, but she suggests DNA is not far behind.
For example, “modifications” can be made to plasmids, and the DNA itself. In some instances, the “bacterial origins of replication” can be eliminated. The effects of these advances are great both for the “cold chain portion of delivery” but also the “cost of manufacturing”. Thus, the overall vaccine product can become “much more accessible”.
As always we love to know what brings our amazing scientist and industry representative to us. For Dr Spiegel, the panel discussion was the big draw. It was an opportunity to discuss some of the ideas she explored in this interview, such as advancing DNA based vaccines, and taking things to the “next stage”. She seemed particularly enthused about working with colleagues to get vaccines to people, particularly children, in “every remote location” with “not much trouble”.
It was a privilege to speak to Dr Spiegel at this year’s event. We look forward to hearing from PharmaJet again in April next year at the World Vaccine Congress in Washington. Get your tickets now to join us there!
In November 2022 the WHO, with “financial support” from USAID, finalised a project on vaccine safety monitoring in Kyrgyzstan. Described as providing support to its government in response to the COVID-19 pandemic, it focused on “adapting and implementing regulatory pathways and procedures” for public health emergencies. It further “strengthened the pharmacovigilance, monitoring, and surveillance of adverse effects following immunisation (AEFI)”.
High standards for all
Promoting the notion of “shared responsibility” the WHO statement indicates that vaccine safety monitoring in Kyrgyzstan is covered by several stakeholders, including the National Immunisation Programme and the National Regulatory Authority for Medicines. Among the achievements of the project was the “establishment of client follow-up and self-reporting systems on AEFI”.
Recording and monitoring AEFI against COVID-19 has taken place since March 2021, with the development of an electronic database. This was integrated with the national system for registering vaccinated persons. Consequently, more than 2109 AEFI could be registered in the system by September 2022. Validated AEFI were shared with the WHO database, VigiBase.
VigiBase is a “unique” global database of potential side effects for medicinal products. It contains over 30 million reports of suspected adverse effects and is continuously updated. Its purpose is to ensure that medicine-related safety problems are quickly identified.
In Kyrgyzstan more than 800 health care workers were trained in the “surveillance and reporting” of AEFI against COVID-19 and pharmacovigilance. Furthermore, over 100 experts from the Department of Medicine and Medical Devices were trained in “vaccines and medicines regulation”.
“Training was provided by recognised experts, including from the Eurasian Economic Union, and capacity-building training on causality assessment of adverse effects following immunisation and adverse drug reactions was also conducted.”
Internal strength: legislation, policy, and coordination
During the project, revisions were made to the regulatory framework for reporting, surveillance, and monitoring of AEFI. Results of the procurement and supply chain management system assessment and the evaluation of state drug policy for 2016-2020 were “communicated”
“These are building on the foundation for the future development of the strategy document on medicines, vaccines, and medical devices regulation, including in emergencies.”
WHO states that one of the “main objectives” was to “build institutional capacity in vaccine development management, and regulatory mechanisms”. Furthermore, preparation for coordination within “future activities” was developed.
The announcement comes just days after the WHO’s publication of the Global Vaccine Market Report 2022 in which national regulatory and development efforts were promoted. If you would like to hear more about legislation and regulatory importance then get your tickets to the World Vaccine Congress in Washington 2022.
Reported by Epicentre, a group “embedded” in Médecins sans frontières (MSF), progress is being made in a joint vaccination effort in South Sudan. Alongside this vaccination campaign is an Epicentre study to “evaluate the effectiveness in real conditions” of the vaccine that has demonstrated promise in clinical trials. It has been recommended for use in outbreak responses by the WHO since 2015.
The WHO describes hepatitis E as an inflammation of the liver caused by infection with the hepatitis E virus (HEV). An estimated 20 million HEV infections each year cause around 3.3 million symptomatic cases of hepatitis E. The WHO also estimates that hepatitis E caused around 44,000 deaths in 2015.
The virus is transmitted through the faecal-oral route, largely through contaminated water. It is prevalent in East and South Asia but exists worldwide. Large outbreaks occur in situations where water and sanitation are inadequate, such as in mass displacement camps. With no specific treatment for hepatitis E, it has a fatality rate of up to 25% among pregnant patients and increases the risk of spontaneous abortions and stillbirths. Although there is a vaccine in China, it is not yet available elsewhere. The vaccine, Hecolin, has been shown highly effective in clinical trials.
Dr Monica Rull, Medical Director of MSF, describes the fight against hepatitis E as “long and frustrating”. In recent decades MSF has responded to outbreaks in displacement camps, attempting to “control the disease in challenging conditions”. It is made harder by seeing the “devastating impact on extremely vulnerable communities”.
“With the experience of this vaccination campaign, we hope to change the way we tackle hepatitis E in the future”.
Bentiu camp is in Unity State, South Sudan. It was established in 2013 and has around 112,000 people. Hepatitis E outbreaks began in 2015 and worsened in 2021 due to “extreme flooding” and an increase in displaced people. MSF has a hospital in the camp and has seen 759 confirmed cases, with the unfortunate deaths of 17 patients.
The Ministry of Health of South Sudan requested that MSF help efforts to control the outbreak through a large-scale vaccination campaign. Although Hecolin has been recommended for outbreak responses by WHO, this is the first time it has been used in response to a public health emergency.
Real time, real conditions
Alongside the mass vaccination programme, Epicentre is studying “coverage and acceptance” as well as the effectiveness and safety of the vaccine. Dr Robin Nesbitt, an epidemiologist at Epicentre, suggests that 91% of the target, 24,469 people, received the first dose of the vaccine in March 2022. 95% received the second dose in April 2022. It is hoped that generating this additional data through ongoing studies will “allay some fears associated with the introduction of newer vaccines”. Furthermore, Epicentre aims to contribute to the “relatively sparse data” on the vaccine in pregnant women, who “suffer the most serious consequences” of infection.
Dr John Rumunu of the South Sudan Ministry of health observed the “successful implementation and the community’s enthusiastic response”.
“I hope the vaccine will help reduce infections and deaths from hepatitis E in Bentiu and beyond.”
The collaboration between the Ministry of Health and MSF will complement outbreak control measures, such as improving water and sanitation services. Additionally, MSF hopes the campaign will “encourage other countries to use the vaccine” in the future to address any further outbreaks.
For more on hepatitis at the World Vaccine and Immunotherapy Congress in San Diego 2022 get your tickets now.
In November 2022 the WHO shared its Global Market Vaccine Report for the year 2022. It is the “first report to capture the implications of COVID-19″ on vaccine markets. It also highlights the “dynamics” that are at play that prevent or hinder the “development, supply, and access” of vital vaccines. In this post we unpack the report and examine some of the calls to action for the future.
The report begins with a foreword by Dr Tedros Adhanom Ghebreyesus. He describes immunisation as one of the “most iconic global health success stories”. However, this is denied to millions of people across the world as access continues to be a major barrier. For example, 20 million infants miss out on key vaccinations each year. Although COVID-19 “reminded the world of the immeasurable power of vaccines as key public goods” it also served as a reminder of “inequities in access” that are the “rule rather than the exception globally”.
Dr Tedros identifies the HPV vaccine as an example of this, introduced in “only 41% of lower-income countries”. In 83% of high-income countries, it is “saving lives”. Clearly the implication is not that we need to strip it back from these high-income countries but accelerate and improve efforts to raise the percentage across the world.
“We will not recover from the historic backsliding in essential immunisation if we continue to allow market dynamics alone to shape global vaccine priorities. Nor will we achieve equitable access to vaccines globally unless we have more transparency and active government oversight.”
Dr Tedros calls for a “more favourable intellectual property landscape” and “proactive technology transfers” as well as increased “building and retention of technical, manufacturing, and regulatory capacity in every region”. We have seen great strides in this direction in recent months in Africa, but the importance of maintaining momentum on this front is evident.
“WHO is calling on governments, industry, international institutions and partners to act now to improve sustainable and equitable access to vaccines. I trust this report will also be used to inform ongoing negotiations on a new international accord on pandemic prevention, preparedness and response, which will allow us to respond to and end future pandemics rapidly.”
Ups, downs, and pandemics
The report continues with a summary of “important progress” and “significant challenges”. For example, there were “many new vaccines developed” such as meningococcal meningitis A, and malaria, which “translate into millions of lives saved”. However, not every dangerous disease is associated with markets of commercial value. They therefore remain “neglected”.
Although there is an “expanding manufacturing base”, with over 90 manufacturers supplying vaccines to Member States in 2021, supply continues to be “highly dependent on fewer than 10 manufacturers”. Additionally, for specific vaccines, a couple of vaccine suppliers dominate the scene. Despite “positive” trends, the “African and Eastern Mediterranean Regions” experience “market health issues and regional supply insecurity”.
More effort (and investment) is also needed to facilitate broader vaccination programmes and “counter the growing threat of vaccine hesitancy”. What we can learn from COVID-19 is that “some of these challenges can be overcome”. For example, the rapid development of vaccines with “innovative technology platforms” came as a result of “unprecedented public investment” as well as “investment in clinical development and manufacturing capacity, and the streamlining of regulatory processes”.
“This incredible achievement in the face of a public health emergency of international concern made stark the long-standing need to reconsider the value of vaccines as a fundamental and cost-effective public good rather than a commodity.”
However, alongside recognised successes during the pandemic, there have been “highly problematic” access issues due to “dynamics repeatedly experienced in other vaccine markets”. Take the “lack of transparency along the value chain of vaccine manufacturing and distribution, and the lack of government oversight” for example, which made it difficult for governments to implement vaccination programmes nationally and internationally.
“We need to enhance government oversight of vaccine production and distribution and strike a much better balance between serving national interests and global public health objectives.”
How can we do this? The report indicates that the “only means” to this is “high-level diplomacy” and “pre-defined and binding rules”. Taking on board the lessons we were taught by the pandemic, we have an “opportunity” to “establish a new paradigm for vaccine development and access”.
As part of this, the following government commitments are recommended:
Establish early, evidence-informed strategic goals and leadership that serve the collective global health interest and to shoulder risks and invest aggressively in order to address the needs of today and prepare for future emergencies.
Strengthen market preparedness by investing in new vaccine technologies, regional research and development and manufacturing hubs, and by enabling regulatory harmonisation.
Ensure transparency and oversight along the vaccine value chain towards enhanced health impact, as well as define principles and operational mechanisms for collaboration across countries in times of scarcity, including for intellectual property and the circulation of inputs and goods.
Industry is called upon with the following commitments:
Ensure that activities are aligned with WHO’s guidance: research and development efforts focused on the WHO list of priority pathogens and target product profiles, more clinical trials performed in low-income countries, and targeted to inform global policy needs and expedited data submissions for regulatory approvals and prequalification.
Establish provisions for technology transfer and ensure transparency along the vaccine value chain.
Commit to specific measures allowing for equity-driven allocation of products.
Finally, international organisations and partners are asked to commit to:
Prioritise the achievement of global public health priorities as per the Immunisation Agenda 2030 as an umbrella for individual organisational strategies, priorities and interests.
Support country-driven initiatives and projects consistently with organisations’ missions and avoid the creation of duplicate efforts.
Continue to call for technology transfer and for the application of resolutions on market transparency for health products.
Vaccine portfolio and regulation
The key takeaway from this section is that “significant progress has been achieved in the development of new vaccines”, but that “diseases associated with markets with less commercial value remain neglected”. Diseases that “primarily affect lower-income countries” have been addressed.
Secondly, COVID-19 proved that with “large public investments, joint planning of clinical development, regulation and manufacturing capacity, and leveraging innovative platforms”. The report suggests that “political pressure” contributed to the amazing work in developing COVID-19 vaccines at breakneck speed. However, before the emergence of COVID-19, work on viral-vectored platforms could be “quickly leveraged”. This innovative work is “set to increase in the coming years”.
Regulation remains a challenge, despite “years of harmonisation efforts”.
“Vaccines are medical products that are routinely administered to healthy people, and, as a result, real or perceived quality issues can compromise trust in immunisation, rapidly erasing progress”.
Thus, “quality assurance” is critical to vaccine development. During the pandemic, we made progress in regulatory “strengthening and harmonisation”. However, the “divergence in vaccine registration requirements” across the world has been highlighted. Filling gaps is particularly “cumbersome for manufacturers in developing countries”, which creates further access issues. In markets with “less commercial value” delays are caused by “suboptimal investment and few pipeline products”. Diseases prioritised by the WHO R&D Blueprint, are “still missing a vaccine”. For the Africa, Eastern Mediterranean, and South-East Asian regions, there is tension between “demographics” and “market value”.
Although manufacturers continue to emerge and grow across the world, the supply base remains “highly concentrated”. The report cites “country data”, which indicate that 10 manufacturers provide 70% of non-COVID-19 vaccine doses and 85% of the global value. Some “clear causes” are identified: vaccine development has “high costs of entry” and yields “lower profits relative to the entry costs” in comparison with other pharmaceutical products”.
What does this mean for market health? For “high impact” vaccines, each market is “highly dependent on one or two manufacturers”. Furthermore, for 6 vaccines that may be needed in emergencies, the health market is “concerning”. On top of this, manufacturing bases are located mostly in the “European Union, Indonesia, Japan, and the United States of America”.
Demand puts further pressure on vaccine supply, and this has had consequences throughout vaccine history. Examples include shortages of the HPV vaccines and inactivated polio vaccines. Although “technology transfer” and manufacturing changes can tackle these issues, they are “costly and take time”. To counteract this, “large public contracts” and “guarantee of purchase” have made a “significant difference”. The vaccine market, the report suggests, is “highly complex” and therefore “less attractive”.
The market requires “advanced know-how”
It is protected by intellectual property rights.
Expansion of capacity “implies non-linear production costs”.
Demand is “very uncertain”.
Allocation of scarce supply
This section suggests that in order to promote “equitable and efficient distribution of vaccines” within and across borders we need a “much higher level of transparency, public oversight over production and distribution, commitment from manufacturers, and high-level diplomacy”.
Another lesson that COVID-19 taught us is that “governments could have played a more active role” in overseeing vaccine supply”. Without this oversight, leaders found themselves in difficult positions regarding “informed, rapid, and strategic decisions”.
“Inequitable distribution, although not unique to COVID-19 vaccines, was a moral and global security failure with health and economic consequences.”
With “substantial progress” towards vaccine equity through initiatives such as the PAHO Revolving Fund, UNICEF, and Gavi, there are still constraints. This is particularly important in paediatric vaccines. COVAX reminded us that “financing and procurement mechanisms” cannot achieve equitable vaccine distribution alone. Despite efforts to “coordinate global demand and supply”, most volumes have “sat outside” the Facility.
“We need to strike a much better balance between serving national interests, global public health objectives and commercial interests.”
Country demand for vaccines
Central to guiding investments is “predictable country demand”. Thus, in “tackling affordability, planning and procurement issues, and by boosting political will and fortifying health systems” we might be able to enhance its predictability. The causes for unpredictable vaccine demand across countries supposedly range from “insufficient political will to inadequate infrastructure and market segmentation due to different products”.
Attempts to address demand issues are both global and regional. For example, “pooled procurement attaints lower prices for 14 of the 18 vaccines most widely used in middle-income countries” compared to self-procurement.
Conclusions and calls to action
As explored above in the early suggestions section, the report contains a call for stakeholders to “assume their shared but differentiated responsibilities”. With suggestions for government, industry, and international organisations, the hope is that this paradigm will serve “both equity and national interests” through a “more coordinated and more equitable global response”.
For full access to the report click here, and make sure you get your tickets to join us at the World Vaccine Congress in Washington 2023 to hear more about vaccine equity and market dynamics.
A study by researchers led by the University of Houston demonstrates potential to eliminate the high caused by the synthetic opioid fentanyl. The hope that it will block its ability to enter the brain has positive implications for tackling a widespread opioid epidemic. Although Opioid Use Disorder (OUD) is treatable, up to 80% of patients with a dependency on the drug experience a relapse. The publication in Pharmaceutics states that the data support “further clinical development of [the] vaccine to address OUD in humans”.
An opioid epidemic
The authors reflect in their publication that a “significant public health crisis” has been caused by “illicit synthetic opioid use”. Between 2019 and 2020 overdose deaths in the US increased to the “highest ever recorded” at 81,000, and more recent statistics are “even higher”. So, what is driving this?
“Fentanyl (FEN) is a synthetic opioid agonist that is approximately 100 times more potent than morphine.”
It is “decidedly lipophilic” and quickly enters the central nervous system, activating mesocorticolimbic circuitry to produce “highly reinforcing euphoria”. The study reports that in the early 2000s there was a significant rise in overdose deaths. This showed that “FEN and its derivatives adulterated other misused substances that led to increased lethality”. Furthermore, between 2010 and 2016 more than 50% of stimulant-related overdose deaths involved it.
Current treatments are effective based on formulation, compliance, access, and the opioid in question; FEN is a “particular treatment challenge” because of its “pharmacodynamics”. This challenge can be addressed with immunotherapies that prevent FEN from entering the brain, thus “pre-emptively circumventing its reinforcing and overdose effects”.
With “poor medication compliance” OUD has almost 90% relapse rates. The authors believe that vaccine immunotherapy could address this by demanding a less intense administration schedule.
“Vaccine immunotherapy targets small molecule antigens such as opioid compounds consisting of the antigen (hapten) linked to an immunogenic carrier protein that stimulates the immune system to generate antibodies.”
An adjuvant is often added to increase immunogenicity. Then, post-vaccination, when an opioid is consumed, antibodies “prevent it from getting into the brain or affecting other organs”. This vaccine comprises a “FEN-like hapten containing a linker with a carboxyl moiety suitable for carbodiimide coupling chemistry to form amide bonds to lysine residues on the carrier protein CRM197, a genetically deactivated diphtheria toxin contained in several FDA-approved conjugate vaccines”.
The study in rats
The study involved 60 Sprague Dawley rats. 32 were used for the schedule-controlled responding experiments and 28 were used for the physiology experiment. FEN was then obtained, as well as morphine, and both were dissolved in sterile saline and administered subcutaneously.
The vaccine formulation was prepared “immediately before administration”. Animals were injected at 0, 3, and 6 weeks. Blood samples were then collected during weeks 4, 6, 8, and 10 post-initial vaccination.
The conclusion states that the vaccine “produced significant amounts of anti-FEN antibodies” in both sexes. It also reduced FEN entry into the brain. The results “warrant further development as a potential therapeutic for OUD and overdose in humans”, with minimal side effects expected.
Lead author Dr Colin Haile describes this study as having “significant impact”. The vaccine’s ability to prevent FEN from entering the brain will subsequently prevent “euphoric effects” and promote an easier road to “sobriety”. Furthermore, the anti-FEN antibodies “did not cross-react with other opioids”, meaning a vaccinated person would “still be able to be treated for pain relief with other opioids”. For Dr Therese Kosten, this vaccine could be a “game changer”.
For more on adjuvanted opioid vaccines at the World Vaccine Congress in Washington 2023 get your tickets now.
“Pioneering a new era of human health”, scientists at the Human Immune Project are tackling “one of the greatest remaining frontiers”: the human immune system. Formerly known as the Human Vaccines Project, and modelled after the Human Genome Project, they are “unlocking the mechanisms of human immunity”. Their aim is to “transform how we fight our most devastating diseases” and their methods combine systems biology and artificial intelligence. In this piece we take a closer look at who they are and what they do.
The future of immunity
The HIP identifies a major challenge in vaccine research: the “limits of scientific knowledge”. Fighting “insidious and biologically complex diseases” is no mean feat, and examples of HIV, tuberculosis, and various cancers underpin the difficulty we face. Furthermore, as we prepare blindly for the next pandemic, we can only make (reasonably scientific) guesses at what it might bring.
“A new approach is necessary now, one that is rooted in identifying and understanding the common elements of the human immune system that overlap across global populations and that allow us to harness this knowledge and the collective intelligence of scientists”
Recognising this need, the HIP is putting “breakthrough advances in biomedicine merged with AI” into the hands of the “world’s top scientists”. Across a worldwide network, partners are “compiling the biggest dataset of biomedicine at a population scale”. With this, an AI model of the immune system can be created, to accelerate and reduce the cost of vaccine and treatment development.
“Our goal is nothing short of enabling people to live much healthier – and longer – lives.”
A helping hand from AI
Dr Wayne Koff is the President and CEO of the Human Immunome Project. He describes everyone’s immune system as “unique” but asks why vaccines can be 90% effective at protecting against disease.
“Our task is to develop a model or a series of models that will eventually be able to explain this and that will eventually allow us to predict how the immune system will respond to pathogens, vaccines, drugs, and immunotherapies.”
The task will be made possible with the power of AI and deep learning. A platform known as AlphaFold is already solving protein structures in rapid time. Further possibilities include ever improving interpretation of retinal imaging to predict risks of disease. For Dr Koff, this is “extraordinary”.
“All of this is giving us new opportunities.”
Writing for the Human Immunome Project, Kristen Jill Abboud suggests that AI can “accelerate and vastly improve the use of in silico studies to prioritise vaccines or therapies without the need for large clinical trials”. The Project is therefore working to “develop and implement” a plan with partners. The future looks bright for the project but will need careful consideration and collaboration. Part of this will involve a “consensus on how immunome data should be generated, accessed, and managed”. With “social and ethical implications”, the project certainly has its work cut out!
A study in JAMA Oncology in November 2022 suggests that researchers in the US are making progress with an experimental vaccine against breast cancer. Led by Dr Mary (Nora) L. Disis of the University of Washington Medicine Cancer Vaccine Institute, the team indicate success in Phase I clinical trials.
The WHO states that 2.3 million women were diagnosed with breast cancer in 2020. The NHS estimates that 1 in 8 women are diagnosed with the cancer throughout their lifetime. Many are over the age of 50, but not all. Only 1% of breast cancer diagnoses occur in male patients. Dr Kotryna Temcinaite of Breast Cancer Now told Medical News Today that it is not a “single disease, which makes it more difficult to treat”.
“There are many types of breast cancer and treatments that work well for some people, may not work as well for others.”
Calling for “kinder and smarter” treatments, she indicated the importance of “further research” into the disease. Dr Disis, lead author of the recent study, explained that current treatments often lead to “disease recurrence” when a small amount of cancer remains undetected. Thus, vaccines are required to fill the gap.
“Vaccines will stimulate t-cells which can be programmed to hunt down these last remaining cells in the body and kill them. Stimulating effective immunity is the only way I know we can sterilise the body from all breast cancer cells.”
UW’s Phase I trial
The trial was a nonrandomised clinical trial of 66 patients with “advanced-stage ERBB2-positive breast cancer”. Formally known as HER2, ERBB22 is a key tumour protein. High levels of ERBB2-specific type 1 T cells are “associated with favourable clinical outcomes after trastuzumab therapy”. Unfortunately, only a “minority of patients develop measurable ERBB2 immunity after treatment”.
The researchers determined to assess the safety and immunogenicity of 3 doses of a plasmid-based vaccine, which encoded the ERBB2 intracellular domain. Over two periods, 2012-2013, and 2021-2022, they collected and analysed data. The vaccine was “administered intradermally once a month” with “soluble granulocyte-macrophage colony-stimulating factor as an adjuvant for 3 immunisations”. Medical News Today reports that the most common side effects associated with the injection were flu-like symptoms and fatigue.
“Participants who received the higher vaccine doses of 100 μg and 500 μg demonstrated a stronger immune response than those who received the 10ug dose, but there was no significant difference between the immune responses to the 100ug and 500ug doses.”
The future of vaccines
Dr Disis hopes there is a “good chance” that we will see breast cancer vaccines in about 5 years. Many groups are “working on ‘next-gen’ vaccines with very effective delivery technologies and adjuvants” she says. However, this progress is not limited to breast cancer. A range of possibilities are being explored in Washington alone, with programmes including ovarian cancer, colon cancer, and prostate cancer.
For this vaccine, the next step is to “formally test” the observations of this study to see if it does “prevent disease recurrence”.
In November 2022 CEPI and the University of California, Davis announced a partnership agreement to “advance and expand the application of ‘SpillOver’”. This is a viral ranking app that compares the risks presented by animal and human viruses. With funding from CEPI the app will go to the “next level”.
The database reportedly ranks hundreds of “virus, host, and environmental risk factors” to identify viruses with the highest risk of zoonotic spillover. UC Davis researchers developed the open database with data from 509,721 samples from 74,635 animals across 28 countries and public records. Then, the data were used to “rank the spillover potential” of 887 wildlife viruses.
With up to US$1.76 million from CEPI, the app’s database will expand to include “new risk factors”. These include viruses that infect domesticated animals or those “harboured by reptiles and amphibians”. The UC Davis One Health Institute will also “pioneer a new system” with the support of artificial intelligence, to analyse “multiple sources” in search of data.
Viral top trumps
Recent findings published in PNAS and based on over 30 risk factors indicate that Lassa virus is the highest risk pathogen after SARS-CoV-2. There are currently no licensed vaccines against Lassa fever, but a collaboration between IAVI and CEPI aims to address this.
As well as developing vaccines against known diseases, CEPI states that it is possible to develop “prototype vaccines” against different virus families. These can then be adapted quickly as a new virus is identified. CEPI hopes to build a ‘library’ of vaccine candidates in time for Disease X. This is part of the $3.5 billion 100 Days Mission, a “plan to compress vaccine development timelines to 100 days”.
Dr Melanie Saville, Executive Director of Vaccine Research and Development at CEPI, suggests that “most viruses that cause disease in people are descended from one of around 25 families”.
“There are viruses out there that we don’t yet know about, also known as Disease X, but which are likely to come from one of these 25 or so viral families”.
Through the partnership with UC Davis CEPI hopes to “home in” on these viral families. Thanks to globalisation, we are more “vulnerable to the rapid spread of new zoonoses”. Thus, the identification of “another pandemic disease” is predicted to come any time soon. Additionally, the risk is “further heightened by our warming climate”, which expands the range of disease-carrying creatures and increases their interaction with human populations. Dr Jonna Mazet of UC Davis is “thrilled” to be collaborating with CEPI to “create a healthier future for us all”.
“Together we will use cutting-edge methods to dramatically increase the amount virus data available for risk ranking. This is a critical step forward in streamlining vaccine pipelines with the power to revolutionise epidemic and pandemic preparedness.”
For more on preparation for Disease X at the World Vaccine Congress in Washington 2023, get your tickets now.
Another highlight from this year’s World Vaccine Congress in Europe was the opportunity to speak to Dr Christian Brander in person. Co-founder and Chief Scientific Officer at Aelix Therapeutics; he and his team are based in Spain, focusing on a therapeutic HIV vaccine. His presentation at the Congress explored some of Aelix Therapeutics’ recent results, and we were lucky to steal some of his time for a conversation.
Introducing Aelix Therapeutics
Dr Brander kindly explained who he is and what his current role is for those of us who are unfamiliar with the team at Aelix Therapeutics. He believes that his roles as Chief Scientific Officer and ICREA Research Professor complement each other and contribute to “recent success” in the clinical programme. Aelix Therapeutics is dedicated to the development of a therapeutic HIV vaccine for use in cure/eradication stages.
What did you bring to the Congress?
We asked more about Dr Brander’s showcase at the Congress, and he indicated that he was sharing limited data due to a paper embargo at Nature Medicine. Therefore, he was able to give insights into the safety and efficacy data from the recent 002 clinical trial, a “double blind placebo controlled” trial in patients whose infection was quickly identified and “immediately treated”.
How did you operate during COVID-19?
As ever, we were interested to learn how Aelix Therapeutics fared during the pandemic, and to what extent research was affected. Dr Brander suggested that “at the height of the COVID outbreak in Spain” Aelix Therapeutics conducted 002 and 003. Luckily, thanks to “corrective measures” such as home visits and early vaccinations, no participants were lost. Despite the “severe impact on day-to-day operations” the team pulled through. It is remarkable to hear from so many of our speakers how they were able to rise to the challenges presented by the pandemic.
Although COVID-19 presented a unique set of obstacles to the development of Aelix Therapeutics’ vaccine, T-cell vaccines bring their own challenges. For HIV infection, Dr Brander sees the need for a “combination approach”. This necessitates testing a vaccine alongside “other components that [they] think can complement” it. Thus, large trials are required, with “large cohorts” across “different arms”.
At this stage, Dr Brander and his team have “massively de-risked” the T-cell immunogen platform in order to “go confidently” into combination trials.
Those of you who have been following previous interviews will know that we love to ask about our events. Apart from the ego boost, it is helpful to understand what really draws our world-class speakers to the Congress. Dr Brander served us a slice of humble pie on this occasion, remarking that being “close to home” is ideal! He reflected that getting to “sleep in [his] own bed” after a “day of fantastic talks” is a winning factor. However, he also identified that “contacts and matchmaking” make it a “great place”.
Thank you to Dr Brander for making the time to speak to us, and for giving us an insight into the development of HIV therapies. If you are interested in learning more about HIV programmes you can join us either in San Diego or Washington by getting tickets now.
On 8th November 2022 the WHO and the 5 members of the World Health Professions Alliance (WHPA) signed a memorandum of understanding to “enhance” their collaboration on “protecting and investing in the health workforce”.
The WHPA includes the FDI World Dental Federation (FDI), the International Pharmaceutical Federation (FIP), International Council of Nurses (ICN), World Physiotherapy, and the World Medical Association (WMA). Collectively, they represent over 41 million health professionals. Furthermore, they bring “essential knowledge and experience” from “key health professions” in more than 130 countries. Dr Tedros Adhanom Ghebreyesus, Director-General of the WHO, hopes the memorandum of understanding will “support health care professional associations and governments”.
“There is no health without health workers.”
He hopes that the memorandum will ensure the protection of and investment in the “multi-disciplinary teams of health workers” required to “deliver essential health services and prevent and respond to emergencies”.
The memorandum of understanding was described by the WHO as reflecting the “importance of investing in the health workforce through a multi-stakeholder integrated approach”.
“It provides a framework for joint action”
Specific intentions include collaboration on “priority health workforce issues” as well as “universal health coverage, noncommunicable diseases, and ageing populations”. Both the WHPA and WHO have continued to pursue “common goals” throughout the pandemic, including vaccination of health workers and stronger health systems. Enzo Bondioni is Chair of the WHPA and Executive Director of FDI. He hopes that we will learn from the COVID-19 pandemic that “today’s public health problems cannot be solved by one country or one organisation or one profession by itself”.
“Through collaboration between stakeholders we can tackle interlinked global health challenges by taking joint action to protect and strengthen the health workforce and make progress towards universal health coverage.”
Some of the key issues facing the WHPA and WHO include health worker safety in dangerous or hard-to-reach locations and effective education and support for health workers across the globe. As we continue to emerge from the sustained effects of the COVID-19 pandemic, health workers remain on the ‘front line’ of the fight.
A publication in the Journal for ImmunoTherapy of Cancer in October 2022 by researchers at the Leiden University Medical Centre (LUMC) investigated the safety and immunogencity of ISA Pharmaceuticals’ Amplivant adjuvant and Synthetic Long Peptide (SLP) therapeutic vaccine technology. ISA stated in November 2022 that it is “delighted” with the publication, which demonstrates a “favourable safety profile”. The study was expanded from initial approval to enrol oropharyngeal squamous cell carcinoma (OPSCC) patients after “treatment with curative intent” to include patients with “an HPV16 positive (pre-)malignant lesion following standard treatment”.
The study in context
The authors of the publication note that “cancer vaccines are a promising strategy for cancer immunotherapy”. Furthermore, SLP based cancer vaccines are “safe, able to induce functional tumour-specific T cells, and show clinical efficacy”. However, they require combination treatments because they have “no intrinsic adjuvant”. Preclinical studies had revealed that “chemically well-defined adjuvants” such as Toll-like receptor (TLR) ligands can improve synthetic peptide cancer vaccines.
ISA’s Amplivant is one such ligand, which is “chemically adapted to optimally interact with the binding domain of the TLR2/TL1 heterodimer receptor to induce improved immunological activity”.
“Molecularly defined, self-adjuvanting peptide vaccines have the potency to cause local innate immune activation, antigen-targeting to dendritic cells (DCs) and DC activation, together leading to efficient T cell activation.”
In order to explore to potency of Amplivant-conjugated SLP vaccines the researchers used SLP derived from the human papilloma virus type 16 (HPV16) E6 oncoprotein amino acid (aa) sequence. Previous studies have demonstrated that spontaneous HPV16-specific T cell responses “occur but are weak” and unable to control tumour outgrowth.
The study is the first in human Phase I trial to establish safety and immunogenicity of Amplivant conjugated to HPV16 E6-SLP. Administered intradermally to take advantage of the “direct loading potency of skin-resident DCs”, the vaccine was injected 3 times in 4 dose cohorts. Between 2015 and 2020, 25 patients were enrolled.
“Patients were eligible for inclusion if they were at least 18 years of age, had previously documented evidence of an HPV16 positive (pre-)malignant lesion following standard curative treatment and were without residual disease based on physical examination between 4 and 16 weeks after therapy.”
Further inclusion criteria were applied. The vaccine comprised two HPV 16 E6 SLOP sequences, and the Amplivant-conjugated SLPs were manufactured and tested in The Netherlands. The trial included 2 weeks of screening, 6 weeks of vaccination treatment, and follow-up visits throughout the 20 weeks after the final dose of the vaccine.
Conclusions and limitations
The authors state that the study shows the vaccine to be “safe with only minimal and mostly local side effects”. In this study, CD4+ T cell responses were “more frequently found compared with CD8+ T cell responses”. This is “consistent” with previous results.
The authors note that “trial set up and patient availability” caused an “unfortunately unbalanced” male-female ratio. Despite this, they believe that the “unintentionally skewed” ratio didn’t influence response outcomes.
As we continue sharing interviews that took place during the World Vaccine Congress in Europe 2022 we are also gearing up for our next event, the World Vaccine and Immunotherapy Congress in San Diego in November 2022. In doing so we are delighted to share some exclusive pre-Congress interviews with the community. The first of these is a call with the Director of the AIDS Division at NIAID in the US. Dr Carl Dieffenbach is a highly regarded researcher and team leader who will speaking about pandemic preparedness and bringing HIV/AIDS to an end. We were delighted to claim some of his time for a quick conversation about these concerns.
What does your role involve?
As head of the HIV/AIDS portfolio Dr Dieffenbach has a lot on his plate across a range of areas. Pandemic preparedness is a huge aspect of his work, and he is really keen to emphasise this at the congress. He believes this involves 3 critical components: “vaccines, therapeutics, as well as diagnostics”. However, there is also a “really important bridge between vaccines and therapeutics, and that is the development of neutralising monoclonal antibodies.” In terms of how this fits into Dr Dieffenbach’s role, he is encouraging an “integrated” approach at NIH. Without giving too much away, he indicated that this was coming together in a “pretty good plan”!
From COVID-19 to future pandemics
As with all of our interviewees, Dr Dieffenbach has a useful insight into how we move forward from COVID-19, particularly with regard to a future threat. We asked about gaps in our preparedness for COVID-19, and how we can address them in time for the next threat. For Dr Dieffenbach, preparedness is about “having programmes to a specific stage where you can respond quickly”. For example, with vaccines, we have to have “good platforms” ready for action. In terms of appropriate drugs, we “should” be able to prepare “family specific inhibitors” that then need only a bit of “tweaking” to be effective.
The example Dr Dieffenbach highlights from COVID-19 is Pfizer’s journey to Paxlovid. They had a SARS-1 drug and “went back into medicinal chemistry” to get the active component. This was done effectively, but thanks to a “lot of work in that medicinal space”. Contrasting COVID-19 with Zika virus, we were only so quick in our response to the former because we had a “tremendous amount of experience with coronaviruses”.
The “forgotten” epidemic
Dr Dieffenbach’s role will bring a valuable insight to the Congress this month. We asked about progress in the HIV/AIDS fight and where we need greater efforts. One thing that Dr Dieffenbach made clear is that he and his team did not drop the ball during COVID-19.
“When people talk about the forgotten epidemic, I the only people that have forgotten about it is the press.”
When a new pandemic arrived, researchers were faced with a “fork in the road”. Their decision was to take both paths. Thus, work on HIV continued at speed whilst “infrastructure” was also shifted to support the development of COVID-19 vaccines and therapeutics. This was “incredibly successful”, resulting in the trial of CAB-LA, a potential “game-changer”. Contrasting regular pills with less frequent injections, Dr Dieffenbach thinks that progress was made during the pandemic. However, on the “implementation side” and the “healthcare delivery side”, things have “slipped”.
At the Congress, the “Holy Grail” of HIV research will come up, two key issues that Dr Dieffenbach and his colleagues are trying to tackle. The first is the search for a “safe, effective, and durable vaccine”. The second is a cure that can be developed and implemented in such a way that “people don’t have to take medicine everyday”.
Our penultimate question was about health threats that we are currently facing, and will continue to face for the future. For Dr Dieffenbach, these are the nebulous threats of “complacency”, “disinformation“, and the knowing dissemination of “falsehoods”. In COVID-19 we saw this twofold, with anti-vaccine movements but also drug disinformation around hydroxychloroquine and ivermectin.
“We’re so fact-based and rule-bound about how we respond that if somebody says something outlandish, it’s like, how do you respond to that?”
Dr Dieffenbach looks back to 1918 and the Spanish Flu. There was a “tremendous amount of that kind of behaviour as well”, suggesting that it is “innate”. However, without the inflammatory effects of social media, it could have less of an immediate and impenetrable hold.
This year’s Congress
Our interview concluded with a reflection on the Congress and why it is important. For Dr Dieffenbach, it is “really important to help us understand where we are” on a range of diseases. It is also about “innovation”, and communication between industry, academia, and innovators.
It was a privilege to speak to Dr Dieffenbach during his busy working day, and we are so excited to hear more from him later this month. If you would like to join us at the Congress, get your tickets here! We will also be focusing on HIV/AIDS at the World Vaccine Congress in Washington next year so do get tickets for that!
A November press release from GSK indicates a rise in revenue and profit, attributed to its Shingrix vaccine for shingles. Pharmaphorum suggests that, since the “spin-off” from Haleon in July it has “exceeded analysts’ estimates”.
GSK recorded an 18% increase in revenue to £7.8 billion and an 18% operating profit increase to £2.6 billion. It now predicts further sales growth of between 8% and 10%. Pharmaphorum describes how Shingrix “generated sales of £760 million” in the quarter. This is up 51% and “around $75 million ahead of expectations”.
Shingrix is a shingles (herpes zoster) and post-herpetic neuralgia vaccine that the EMA recommends for adults over the age of 50 or for adults at higher risk over the age of 18. The EMA suggests that it is designed to “prevent shingles in people who have been in contact with the varicella zoster virus and have already developed antibodies against the virus”. With surface antigens and an adjuvant, the vaccine is expected to encourage faster antibody development in patients. GSK expects “strong double-digit growth and record sales in 2022” for Shingrix. This is based on demand in existing markets and continued geographical expansion”.
Dame Emma Walmsley, GSK’s CEO, described the quarter’s performance as “excellent”. She looks forwards to “Shingrix global expansion” and “expected new launches including our new RSV vaccine”.
“We are also making good progress to strengthen our early-stage pipeline and will continue to invest in targeted business development to build optionality and support growth in the second half of the decade.”
For more from GSK at the World Vaccine Congress in Washington 2023 get your tickets now.
A study by researchers at the University of Portsmouth in Vaccine at the end of October explored the effects of the COVID-19 pandemic on vaccine confidence. As we have previously explored, vaccine fatigue, vaccine hesitancy, and anti-vaccine disinformation have contributed to lower rates of vaccinations in certain populations. This recent study compares two cross-national surveys with “similar modalities” in 2019 and 2022 to explore changes in vaccine confidence and the links to “specific demographics”.
How did we get here?
Although “vaccination is widely considered to be one of the safest and most effective primary health care measures” it is a hugely contentious subject. In the face of historic successes, such as reductions in typhus, cholera, and plague, and more recent effects such as a “substantial drop in cervical cancer incidence”, large groups remain unsure of or opposed to vaccines.
“Despite overwhelming evidence supporting its importance as a key primary prevention measure, immunisation has been the object of controversy and vocal opposition ever since its inception.”
The authors consider “Wakefield’s infamous article” in 1998 and the “subsequent MMR controversy” but acknowledge that vaccine hesitancy and refusal have their origins in the “early days of variolation, even before the administration of the first vaccine”.
The Strategic Advisory Group of Experts (SAGE) was established in 1999 by the WHO to “provide guidance” on its work. It is the “principal advisory group to WHO for vaccines and immunisation”. In 2011 it proposed the 3Cs Model as determinants of vaccine hesitancy: Confidence, Complacency, and Convenience. As we explore in our post in the 5C model, it has since been expanded by other sources, to include Calculation and Collective responsibility. SAGE frameworks contribute to global national health approaches and vaccination campaigns, most recently to “model hesitancy and refusal of COVID-19 vaccines”.
The authors of the paper reflect that at the time they were writing, “11.9 billion doses” of a COVID-19 had been administered. This corresponds to “61.2% of the global population being” what is contentiously referred to as “fully vaccinated”. However, they do acknowledge “wide variation in vaccination rates” between countries.
“While the rapid development and administration of COVID-19 vaccines are widely considered an extraordinary public health accomplishment, they also spurred considerable controversy and opposition.”
The authors suggest that “confidence” factors seem to be “preponderant”. Misinformation about the safety of these vaccines was particularly problematic. Although there were demonstrated benefits to mass vaccination programmes, The Lancet published an article in 2021 stating that “willingness to vaccinate against COVID-19 has declined” between the “early months of the pandemic” and the end of 2020. Thus, this study aims to ascertain whether public vaccine confidence has fallen “below pre-pandemic levels despite the successful implementation and outcomes” of COVID-19 vaccinations.
Two anonymous online surveys were carried out to “investigate the public perspectives on the practice of vaccination and the factors that might underpin hesitancy and refusal”. The first took place between November and December 2019, just as early cases of the virus were identified in China. The second was distributed in January and February 2022. The questionnaires were “adapted from the WHO SAGE Vaccine Hesitancy Scale”. Most importantly for this study, 10 questions were the same across the surveys.
Overall, 1009 participants were recorded, with demographic “deviations”. However, “both cohorts showed a majority of female, white, young adults”. Within each cohort the study suggests “internal trends were relatively consistent”. Despite these, “irrespective of the participants’ gender, age, graduate status, ethnicity, and religious belief” there was a “decline in vaccine confidence scores following the COVID-19 pandemic”.
“Only approximately 1 in 5 participants of the 2022 cohort self-assessed their vaccine confidence as having increased since the pandemic”.
Although the study is limited, with the lead author Dr Alessandro Siani suggesting to SkyNews it should be “interpreted with a grain of salt”, it does corroborate “other observations suggesting that vaccine confidence may be yet another victim of the COVID-19 pandemic”. Another limitation is the “use of a non-probability sampling strategy”, which means the cohorts were not necessarily “representative of the wider population”. With this in mind, “further investigations are required” to confirm the extent to which this observed reduction in confidence is “representative” of other populations.
The authors conclude that across all demographic groups there was a reduction in confidence but state a “statistically significant association” between “Asian ethnic backgrounds and low vaccine confidence” among other trends. Overall, the general decrease in vaccine confidence implies a decrease in uptake for routine immunisations, childhood immunisations, and protection against future threats.
For more on vaccine views at the World Vaccine Congress in Washington 2023 get your tickets now.
Researchers in Europe published results in Cancer Discovery in November 2022 that indicate promising responses to vaccination with senescent cells. The researchers suggest that these cells “combine several features that render them highly efficient in activating dendritic cells (DCs) and antigen-specific CD8 T cells”. Furthermore, the immune response to this study is “superior to the gold standard of immunogenic cell death”.
The Barcelona Institute for Research in Biomedicine (IRB) states that “senescence is a state of latency reached by damaged or aged cells in which they do not reproduce”. They “emit information signals into their environment”, alerting the immune system to their presence, which stimulates an “inflammatory response and tissue regeneration”.
The team used these cells because of these useful characteristics. As they are living, they stimulate the immune system for longer, but as they don’t divide, they can’t “regenerate the tumour”. Ines Marin is a doctoral student and author of the study who believes their findings are “very positive”.
“Our study concludes that the induction of senescence in tumour cells improves the recognition of these cells by the immune system and it also increases the intensity of the response they generate.”
Next level immune responses
Led by Dr Manuel Serrano and Dr Federico Pietrocola the group explored the effectiveness of senescence in immunisation. The IRB describes how this was a two-pronged approach looking at preventing and improving cancer in mice. As a therapeutic option, although limited by the “protective barrier of the tumour”, some “improvements were also observed”. Dr Serrano explained that this could be a positive step in understanding the immune response.
“Our results indicate that senescent cells are a preferred option when it comes to stimulating the immune system against cancer, and they pave the way to considering vaccination with these cells as a possible therapy.”
The study is supported
Using animal models of melanoma and pancreatic cancer, as well as samples from cancer patients, they found that “human cancer cells also have a greater capacity to activate the immune system when they are previously rendered senescent”. The next step is a combined approach of vaccination and immunotherapy.
This study was published in the same journal as another article that IRB describes as “completed in collaboration with IRB Barcelona”. This reaches “complementary conclusions” from a “different approach”. The work reveals that these senescent cells are better able to “receive” signals from their environment, which “amplifies the anti-tumour effects of signals such as interferon, making tumour cells more visible to the immune system”.
These studies present further potential for cancer therapies, which we know to be a huge task for researchers across the globe. To learn more about progress in cancer and immunotherapies at the World Vaccine Congress in Washington next year, get your tickets now.
Over a month after the declaration of an Ebola outbreak in Uganda in September 2022 the WHO, CEPI, and Gavi issued a statement on the situation. Observing the spread to 7 districts and acknowledging the government-led response, these organisations have “outlined a plan”. The plan will “accelerate research”, “ensure access to investigational doses” and “facilitate scaling up and access to any subsequent licensed vaccine”.
The statement in November 2022 identifies the importance of vaccination in outbreaks such as this one. However, as there are no licensed vaccines or therapeutics for the Sudan ebolavirus, all efforts are being directed towards the candidates that might be suitable.
“By embedding research at the heart of the outbreak response, we can achieve two goals: to evaluate potentially efficacious candidate vaccines, and to potentially contribute to end this outbreak, and protect populations at risk in the future.”
Vaccine and therapeutics trials have been designated to the Makerere University Lung Institute. With support from WHO, CEPI, and Gavi, there should be enough doses for trial “and beyond”. Candidates in consideration include vaccines from the University of Oxford and the Serum Institute of India, and the Sabin Vaccine Institute and BARDA. Further overall support has been offered from organisations such as Africa CDC, UNICEF, and the African Vaccine Regulatory Forum (AVAREF).
A statement of intent
The statement outlined a series of goals that are “likely to evolve” as the outbreak continues.
Short term support to the Ministry of Health of Uganda’s outbreak response, including support of a randomised clinical trial to evaluate vaccine candidates.
Mid-term allocation of resources to “plan for and to reserve sufficient manufacturing capacity” for the scale up of vaccine candidates, potentially through a “risk-sharing mechanism”. This might involve manufacturing additional vaccines during the trial to “ensure that doses of a vaccine found to be efficacious” is readily available.
Longer term exploration of pathways to ensure that licensed SUDV vaccine(s) are available via the Ebola stockpile.
Commitment to a mechanism to “ensure equitable access and funding for SUDV vaccines research, outbreak response, and preventative vaccination”.
The collaborators have committed to be “guided by the following principles”:
Leverage organisational strengths towards a common goal.
Country driven and country engaged.
Decision making which is evidence-informed and considers access.
End-to-end approach based on access and equity.
Efficient resource allocation.
Research integrity and ethics.
As the outbreak continues to claim lives across more areas, the importance of this collaboration is clear. Furthermore, the emphasis on following the leadership of the Ugandan ministries is of note; will they be able to maintain this approach?
For more on tackling Ebola with vaccines come to the World Vaccine Congress in Washington 2023.
From the start of the COVID-19 pandemic it was clear that each of us would have a different experience. When the vaccines were developed in record time, it came as no surprise that “vaccine nationalism” became prevalent. Described by WHO Director General Dr Tedros Adhanom Ghebreyesus as a “me-first approach”, vaccine nationalism is assumed to have caused a needless loss of life across the world. Now, a study in Nature has put a number to it.
The world in numbers
By the end of 2021 the spread of vaccines was heavily imbalanced. Some countries had achieved over 90% coverage in adults, but others had below 2%. As we explored in our post on global vaccination, Africa had the slowest vaccination rate of any continent. In mid 2022 just 25.5% of the population was at single dose.
Hoping to better understand the effect of these inequalities, researchers in the UK used an “age-structured model of SARS-CoV-2 dynamics, matched to national data from 152 countries in 2021”. The aim was to “investigate the global impact of different potential vaccine sharing protocols that attempted to address” the inequity caused by hoarding.
“We found that greater vaccine sharing would have lowered the total global burden of disease, and any associated increases in infections in previously vaccine-rich countries could have been mitigated by reduced relaxation of non-pharmaceutical interventions.”
The authors note that lower-income countries were “mostly dependent” on donations and sharing schemes. This relied on the good will of countries who had already achieved higher levels of coverage. The study reports that although stockpiling or vaccinating and boosting lower risk groups were appealing, sharing vaccines has “markedly higher payoffs per dose in reducing infection and mortality”.
For countries that were able to vaccinate large percentages of their population, restrictions could be relaxed and a “return to pre-pandemic-like” habits was seen. Despite this, the “estimated waning of vaccine efficacy” and emergence of new variants provoked booster campaigns in these areas. Caught between a rock and a hard place, countries had to evaluate the benefits of preventing “high levels of new global infections” by sharing vaccines or playing domestic catch-up with boosters. The model suggests that some “non-pharmaceutical mitigation measures” may have been necessary alternatives to boosters in some areas.
The study is retrospective, but the authors believe that “robust” conclusions can still be drawn. Based on “simulations fitted to historical infection and mortality estimates and from varying the distribution of vaccination between countries while maintaining the total vaccine supply”, their suggestion is that a greater level of vaccine sharing would have seen “sizeable benefits”.
The ugly truth
The study reveals that a “more equitable approach” to vaccine distribution throughout 2021 would have “reduced the level of global mortality associated with COVID-19 disease”. This might have come at the “cost” of “increased or prolonged” non-pharmaceutical interventions.
“In total, we estimate that a full vaccine sharing scenario would have prevented 295.8 million infections and 1.3 million deaths worldwide (as a direct result of COVID-19) by the end of 2021”.
The study has been described as a significant step in pushing for “vaccine coverage” by Dr Oliver Watson at Imperial College London.
“That’s really important for engaging political will and framing big political decisions.”
As we continue moving forward it remains to be seen if we will learn from this evidence and make vaccine equity a priority in the future. Unfortunately, this seems an unlikely prospect, particularly considering recent outbreaks. For example, monkeypox demonstrates a sustained unwillingness to address the “larger reservoir of infection”.
“Our results reinforce the health message, pertinent to future pandemics, that vaccine distribution proportional to wealth, rather than to need, may be detrimental to all.”
For more on vaccine equity at the World Vaccine Congress in Washington 2023, get your tickets now.
In November 2022 a commentary in The Lancet Global Health reflected that COVID-19 vaccination programmes have been “relatively successful” across the Association of Southeast Asian Nations (ASEAN), which now includes 10 member states. According to the authors, these programmes were effective in “blunting the worst of the pandemic and increasing overall public understanding of and support for vaccination programmes”. However, they identify more to be done.
Inspiration from PAHO’s Revolving Fund
The Pan American Health Organisation (PAHO) has a Revolving Fund, which the authors believe to be a “useful reference” for the formation of an ASEAN Vaccines Revolving Fund (AVRF). With the intention of promoting “long-term vaccine procurement” it would start with COVID-19 vaccines and move outwards to “other vaccine-preventable diseases”.
PAHO’s Revolving Fund was founded in 1977 and “pools the resources” of 41 PAHO states. Each year it is estimated to purchase $1.1 billion worth of 47 vaccines and 29 vaccine-related supplies for 15 million people. Furthermore, it is credited with doubling PAHO vaccination rates. The article reports that it was the 1st of 6 WHO regions to be “certified polio free in 1994”. Later, measles and rubella were “eliminated”.
The suggested objectives for the AVRF are threefold:
Coordinate pooled procurement of vaccines in southeast Asian countries
Support country-level delivery
Build capacity for national level public procurement of other goods and services
“A successful AVRF can increase vaccine supplies, reduce the price for new vaccines, accelerate access to new vaccines, and increase vaccination rates and health equity.”
There are four “structural challenges” identified as barriers to vaccine procurement in southeast Asia. The recommended AVRF would “resolve” these as follows:
Providing a “strong negotiating position with vaccine manufacturers” by representing 650 million people across the region.
Modernising procurement through “innovative tools such as value-based purchasing, health technology assessments, demand forecasting, and new types of reimbursement contracts with manufacturers in the short term, while building country-level capacity and harmonising regional standards in the long term”.
Strengthening local vaccine production and creating incentives for local manufacturers to “expand” production.
Supporting member countries to “amortise capital spending on expensive infrastructure such as cold chains and data systems”.
The benefits are also “strategic”, the authors indicate. With greater purchasing power will come greater access to cheaper and more reliable vaccines. Additionally, “consistent access” to vaccines will reduce the “administrative and financial burdens of disease” throughout the region. Finally, they hope that an AVRF would “institutionalise modern practices and reduce corruption risks”.
The authors recognise that an AVRF will be a “multiyear journey”. The first step would be a coalition, “anchored” by the ASEAN Secretariat or other organisation, such as the IVI in South Korea or the National Vaccines Institute in Thailand. Then it would need to partner with a “geopolitically important country”. The hope is that 3 to 5 founding ASEAN countries would offer “crucial mass” across “population, diplomatic, financial, and technical terms”, with other countries following the example.
The article concludes that an AVRF would help assure “stable, predictable, cost-effective, and early access to new vaccines”. Following the lead of PAHO, and using “political will and skill”, an AVRF can be launched.
“Vaccines have been called public health’s best buys, and an AVRF can make these best buys even better”.
For more on international vaccine partnerships at the World Vaccine Congress in Washington 2023, get your tickets here.