Authors:
Javier Casellas, M.D., Ph.D.
Enrique Chacon-Cruz, M.D., MSc
Felicitas Colombo, MPA
One of the current top experts in the field of vaccinology, Prof. Ralf Clemens did not choose vaccinology as his lifelong career plan from the beginning. Rather, vaccinology chose him.
Trained as a physician in Germany, Switzerland and the United States, he specialized in intensive and emergency care. He spent time in a refugee camp in Thailand with 100,000 refugees from Indochina, where he got interested in infectious and tropical diseases and worked with the Mahidol University, in Bangkok, where he was soon appointed visiting professor. His clinical and research interest was on the treatment of malaria and snake bites.
Prof. Clemens has been working in the vaccine industry since 1988 in various senior scientific and business positions. He was global Head of GSK Biologicals’ vaccine development, followed by his role as head of Global Vaccine Development at Novartis, and SVP and head of Development for the Global Vaccine Business Unit at Takeda. During these years, he and his teams developed and brought to licensure more than 25 different vaccines globally.
Nowadays, Prof. Clemens, serves as Senior Advisor to the Bill & Melinda Gates Foundation and is on the managerial and scientific boards of various biotech startups.
How it all started
Reflecting on the last 35 years, when the industry was starting to get serious about vaccine development, Prof. Clemens recalls that the change in vaccine R&D was not evolutionary but revolutionary. He recalls getting his first budget on a napkin big enough to provide all the information needed.
“At that time, there were very little processes and standards. Somebody knew somebody in the company who had some ideas on how to do clinical development and off we started. And then, the next years were determined by building processes, building a team, and implementing things such as IPDP [integrated product development plan], CDP [clinical development plan] and having the ‘end-in-mind’ approach which was mostly unheard of. And, of course, good clinical practices (GCP) and statistical standards became really very important and established a shift in mindset throughout the organization and the vaccine development environment,” says Prof. Clemens.
These initial gaps were obvious throughout the entire industry. Similarly, the regulatory environment was quite different. To give a bit of a flavor on how it all changed in the last decades in vaccine development, he shares that there was no EMA and a regulatory file included often far less than 10.000 subject’s efficacy data, and post licensure commitments of a few thousand individuals. For newer vaccines, the prelicensure efficacy/safety package was close to 65.000 subjects, and post licensure commitments for HPV were up to 200.000 women over up to 10 years. Prof. Clemens recalls that formal cost-effectiveness analyses were almost unheard off and not needed for inclusions in National Immunisation Programs (NIPs).
Nowadays, of course, the landscape has drastically changed. Safety, alongside with efficacy, benefit-risk, and cost-benefit, is a key parameter and an essential part of the development of any novel vaccine.
“So, show me the benefits. Why should I invest in a vaccine compared to other public health measures? Why should I invest in a vaccine compared to safer cars or better roads? And is the incremental costs worth the incremental benefit of an improved existing vaccine as part of its life cycle management? This assessment was in the early days on some people’s radar screen, but not on many,” recalls Prof. Clemens.
He continues to emphasize that Good Clinical Practice (GCP), Standard Operating Procedures (SOPs), and Data and Safety Monitoring Boards (DSMBs) with the right composition and charter are critical to ensuring subject safety and the integrity of data without any doubt. However, one should also critically challenge SOPs and requirements, as they can seem bureaucratic and may increase development time and costs with questionable added value.
“Of course, one needs to ensure the highest level of safety for drugs and vaccines. And SOPs should focus on that, as well as data integrity. But sometimes I have the impression that SOPs are there just for the sake of bureaucratic perfection. Same with manuals – manuals try to predict all eventualities. Accept gaps which do not affect safety or integrity and it makes everybody’s life easier,” he continues.
Currently, to even start thinking about a new vaccine, a thorough development plan on how a vaccine is envisioned, from its inception to its commercialization and accessibility, needs to be meticulously outlined. This includes an assessment of the competitive environment in which the vaccine will, hopefully, enter the market.
“So, the huge change from the very beginning of vaccine development to now is this integrated approach that as soon as there is a research candidate, the entire value chain or development chain is included in decision making: CMC [Chemistry, Manufacturing, and Controls], translational and clinical medicine, regulatory science, manufacturing, market access and policies.” he shares.
And along with it also came processes and documents.
“And I’m not the typical process person, but these processes and documents such as the IPDP, where each and every function has given the input including stage gate criteria, is the blueprint of vaccine and drug development. It’s a live document where periodically adjustments are made,” Prof. Clemens continues, adding that IPDPs should also demonstrate the societal benefit of the project.
He shares that, for each project, other essential documents include a target product profile (TPP) and a regulatory plan as basis for the CDP, along with a commercial plan that includes financials and a market access plan.
“If you don’t have those, you’re really fishing in the dark and you’re just doing development for development. You need to have the end in mind, and the how to get there. That’s my learning,” concludes Prof. Clemens, who has developed over 25 vaccines that were brought to licensure.
Challenging vaccines
When discussing the most challenging vaccines to develop and the lessons learned from those projects, Prof. Clemens’ answer is unequivocal: HIV, HIV, HIV. Next, tuberculosis (TB), dengue, malaria, and herpes simplex virus (HSV).
“When I was at GSK we did three efficacy trials for prophylactic or therapeutic HSV [Herpes Simplex Virus] and all failed. And GSK was not alone, the same happened to Chiron and others. GSK nevertheless did another efficacy trial and just a few weeks ago they announced that a new phase 2 HSV trial also failed, which led them to reconsider the entire program. May be an mRNA with longer persistence, such as self-amplifying mRNA, could have a chance as a therapeutic HSV vaccine,” he shares.
Prof. Clemens’ learnings: “My learning is I’m a huge fan of the protein and VLP [virus-like particle] technology because this is much more predictable. VLP [which enables high-density, multivalent display of antigens in a manner that closely resembles the structure of a virus have been shown to be highly effective, and safe. They can be produced at scale which reduces COGS [Cost of Goods Sold]. The downside is that, as a biological process, it is not as quick as mRNA or vector-based technologies.”
He also reminds us to keep in mind mucosal vaccination, such as oral vaccines. Oral vaccines are attractive due to their ease of delivery. However, in low-middle income countries (LMICs), there is a high incidence of enteropathies that impact the effectiveness of oral vaccines. As a result, vaccine efficacy is often lower in LMICs compared to high-income countries.
Big failures: “Therapeutic vaccines. All big vaccine companies, including GSK, looked to develop therapeutic vaccines, especially using the novel adjuvant systems, but all failed. Ironically, the only vaccine that has therapeutic effects is the well-known BCG for bladder cancer. However, there is hope: the concept of personalized cancer treatment based on mRNA constructs combined with PD-1 inhibitors has recently shown impressive results: Moderna has reported success in melanoma, CureVac in glioblastoma, and BioNTech in melanoma and pancreatic cancer, with efficacy rates of 50% or more.”
However, the prevention of cancer by vaccines is long established. The HBV vaccine has dramatically reduced the incidence of hepatocellular carcinoma, and the HPV vaccine has done the same for cervical cancer. The HPV vaccines represent a success story: when we conducted our efficacy trial in Costa Rica in collaboration with the NIH, we used a three-dose schedule. From that trial, we demonstrated that women who were not compliant and received only two or even one dose had the same protection against cervical cancer as those who received the full three doses. This finding has since been confirmed by various other studies, leading SAGE (Strategic Advisory Group of Experts on Immunization) to recommend considering single-dose HPV vaccination two years ago.
Among Prof. Clemens’ wish list and based on what could be feasible, a TB vaccine would be the top one on his list.
“There are so many vaccines in late-stage development that we must ask ourselves: how do we get all these vaccines into the kids or adolescence or elderly? This is only doable if we focus again, as in the late nineties, on combination vaccines,” he suggests.
Viral vector vaccines against COVID-19
As part of the conversation with Prof. Clemens, it was unavoidable to discuss the thrombotic events associated with the viral vector COVID-19 vaccines. The 2 manufacturers of adenovirus-vector based Covid-19 vaccines exited the market this year as recommendation for use were restricted and sales plummeted.
“That’s a very important question, and I want to offer a bit of a broader answer. In the pandemic it was so important to have a vaccine quickly as the number of infections grew exponentially. Every Covid-19 vaccine platform – inactivated, vectored, mRNA – was safer than to be infected with COVID, specifically if you were in a risk group. ChadOx1 (Chadox) was one of the very first vaccines available and it saved well over 6 million lives, more than any other Covid-19 vaccine,” Prof. Clemens highlights. “The next biggest societal impact was with the inactivated vaccines, which saved 5.5 million lives, followed by mRNA vaccines.”
He underscores that whatever vaccine was available during the pandemic had a highly positive benefit-risk ratio.
“Of course, when you vaccinate millions and millions you might detect events which you could not identify during clinical development which include, for most vaccines, about 35-45.000 subjects because they are so rare. The thrombotic events following Chadox fall into that category,” says Prof. Clemens, who refers to publications from the UK and elsewhere which show an attributable risk for Cerebral Venous Thrombosis (CVT) of 16 per million doses in younger adults and 3 per million doses in older adults, with the risk being higher in females compared to males.
While an increased risk for Cerebral Venous Thrombosis (CVT) has not been observed after vaccination with mRNA vaccines, Prof. Clemens believes that the myocarditis events occurring after mRNA vaccination are being significantly downplayed. According to a passive surveillance study by the CDC involving 196 million people, and based on VAERS safety reporting, the risk for myocarditis following mRNA vaccination with either the Moderna or BioNTech vaccine increased in young men from an expected incidence of about 0.5 per million doses to up to 70 per million doses—an increase by a factor of approximately 140. The risk increase was higher after the second dose compared to the first, generally more pronounced in males than in females, and was most significant in young men up to the age of about 40 years (Oster M, et al. JAMA 2022;327(4): 331-40. doi:10.1001/jama.2021.24110; Table 2). There was no material difference between the Moderna and BioNTech mRNA vaccines.
“But what is the consequence of a vaccine induced myocarditis? While the acute impact is manageable and generally benign in most cases, myocarditis can be an important factor for arrhythmias later in life. We need to remain vigilant, but we should also avoid overstressing these findings,” warns Prof. Clemens, adding that neither individuals nor society benefit from exaggerating these concerns.
Vaccines within 100 days
Recently, CEPI launched the 100 Days Moonshot Initiative to make vaccines available within 100 days during a pandemic, while it took close to one year in the COVID pandemic from the availability of the genome sequence to the first licensing and vaccination. Typically, it takes 5 to 10 years to develop a vaccine. Although developing a vaccine in 100 days may seem almost impossible, Prof. Clemens believes there are no limits to improvements in processes.
“Traditionally, you do the development steps sequentially. In a pandemic, you must do the development in parallel,” he illustrates, adding that the most important consideration is to define what day zero is.
“Day zero is not when you hear for the first time about the pathogen and then a couple of weeks later you get the sequence and then you start your development. The entire concept is based on a pre-pandemic phase and a pandemic phase,” he explains.
In the pre-pandemic phase, five pillars must be established to ensure readiness when an outbreak poses a risk of becoming a pandemic. According to Prof. Clemens, the first and most important pillar is to build libraries of viral vaccines, as the next pandemic is likely to be viral.
“The concept is to build libraries of vaccines for virus families by picking one or two prototypes of that family. You then test this prototype to find out what immune response is needed to neutralize or kill that virus, which vaccine platform is best suited, what are the best animal models, what are the best immune read out tests. You do a clinical phase I or even II study and then put this prototype on hold in the library. One does this for the virus families with the highest risk and likelihood of outbreaks. Cumbersome, costly, but doable,” he highlights.
The second most important pillar in the pre-pandemic phase of development is to improve surveillance and data sharing. Surveillance is a field that is chronically underfunded and underrated. Prof. Clemens is a strong advocate of wastewater surveillance because it can detect viruses much earlier than waiting for clinical cases. However, considering the risk that tourism might decline, there can be hesitation, complacency, and even a conscious withholding of surveillance data.
The third pillar is for clinical trial sites to have the capacity to conduct large-scale efficacy trials across various geographies, especially in LMICs. He emphasizes the importance of keeping these sites “warm” and proposes mechanisms to ensure they remain active and funded.
The fourth pillar, which he believes is not as critical until later in a pandemic when improvements to a vaccine are needed, is identifying potential surrogates of protection. And final pillar is global manufacturing, which introduces a host of challenges.
Prof. Clemens proposes implementing transparent technology transfer agreements in stages. First, he emphasizes the importance of establishing a reliable fill-finish process in LMICs before transferring upstream technologies.
However, a manufacturing site is not a stand-alone solution. The country must have a functional national regulatory agency, and the manufacturer needs to be capable of executing trials, preparing regulatory files, and conducting adequate pharmacovigilance.
Additionally, issues of trust and cost are intrinsic to this conversation. The cost of manufacturing in LMICs is likely to be higher than sourcing from established mass producers. Therefore, would Gavi or UNICEF be willing to pay the incremental cost for this approach? Prof. Clemens recommends developing a realistic plan that starts with the end goals and works up the value chain.
