Charting a course for the expanded application of mRNA vaccine technology

Nucleic Acid Insights 2024; 1(1), 1–8

DOI: 10.18609/nai.2024.001

Published: 9 January
Interview
Myriam Mendila


A pioneer in the development of mRNA technology, CureVac has spent more than two decades in exploring its potential in both prophylactic and therapeutic vaccine settings. David McCall, Senior Editor, Nucleic Acid Insights, discusses the promise of next-generation approaches with Chief Development Officer, Myriam Mendila.



What are you working on right now?

MM: I came to CureVac about 9 months ago. Prior to that, I spent 6 years with Novartis as Chief Medical Officer in Oncology, and before that, I dedicated 15 years to Roche-Genentech. Throughout most of my career, I have focused on oncology products.

mRNA technology has always held great interest for me. Even during my teenage years in biology classes, learning about genetics, DNA replication, transcription into mRNA, and translation into proteins always fascinated me. Today, the realization that we can use this technology in medicine appeals to me immensely. mRNA serves as a command to the cell to produce something, for example a protein or signaling peptide that can fight a disease, so the possibilities are myriad. That is what excites me about this technology and is precisely why I joined CureVac; to deliver on the potential that mRNA holds. I hope to contribute to advancing the science around mRNA technology for medical purposes, accelerating our clinical programs and bringing these innovations to patients as quickly as possible.

Can you give us some more background on CureVac and details of the current R&D pipeline?

MM: CureVac was founded in 2000 and has been pioneering mRNA technology since then, making significant strides in manufacturing mRNA, enhancing its stability and effectiveness in cell transfection, and leveraging its ability to express encoded antigens.

CureVac has also been developing formulations for mRNA delivery. Upon direct injection of mRNA into the bloodstream, the ribonucleases in the blood swiftly degrade it—we have therefore been focusing on carriers such as lipid nanoparticles and lipoplexes to effectively deliver mRNA to cells. I have observed substantial progress in this regard, particularly with the second-generation mRNA backbone. This progress includes enhanced RNA stability, improved protein translation and expression, and increased immunogenicity.

Turning to the R&D pipeline, CureVac is strategically focused on three major therapeutic areas. Firstly, in infectious diseases, we have a collaboration with GlaxoSmithKline. Here, we are developing vaccines for COVID-19, influenza, and a combination of the two. Promising Phase I data from our second-generation mRNA backbone with monovalent vaccines in both COVID-19 and influenza showed that with low doses of mRNA, a significant immunogenicity in patients could be induced at a reasonable tolerability. The COVID-19 vaccine development program has since advanced into Phase II, with a trial that completed enrollment at the end of October 2023. For influenza, while the initial published Phase I data was for a monovalent vaccine, we have since generated a multivalent vaccine that addresses all four influenza strains recommended by the WHO. The platform has evolved to address multiple antigens with the potential to encode up to eight constructs. With the multivalent influenza vaccine, we conducted another Phase I dose escalation study, which had a successful readout. This led to the commencement of a Phase II study at the end of October 2023. This study is progressing well and the data from both Phase II studies should be available at the beginning of next year, triggering the decision of whether to progress to Phase III.

Secondly, we are active in oncology. We acquired a company, Frame Therapeutics, in 2022, which enriched our antigen discovery machinery. Since then, research has been focused on finding the right antigens to encode for a cancer vaccine. Current work concentrates on initiating and preparing for the next round of Phase I trials.

A Phase I trial with our cancer vaccine platform for glioblastoma began in summer 2023—however, this is in effect more of a proof of principle trial designed simply to show that our mRNA backbone works within the setting. The real innovation will come with the enhanced platform based on the antigen discovery research that has been initiated with the neoantigen compositions and constructs. Phase I clinical trials are being prepared in different cancer indications to hopefully enroll patients within the next 18 months.

The third strategic pillar of the pipeline is molecular therapy where mRNA is used to encode for a missing enzyme or signaling peptide or deficient proteins in order to replace the missing element and reconstitute its function. While specific projects cannot be disclosed, we are optimistic about bringing new treatments or indications to the clinic in the upcoming years.

What for you are the chief high-level trends and strategic drivers shaping both the prophylactic and the therapeutic mRNA vaccine spaces as we move into 2024?

MM: Starting with the prophylactic vaccine space, the one key trend is the remarkable effectiveness that continues to be shown by mRNA vaccines. In some areas, they have demonstrated greater efficacy than currently approved medicines. The mRNA platform allows us to address and generate prophylactic vaccines in areas where today’s vaccines fall short.

The second notable trend is the versatility of mRNA. Due to the ability to design proteins by using the genetic code combined with an efficient manufacturing process, mRNA can be employed to develop vaccines against pathogens where other technologies have struggled, including bacterial and fungal pathogens. Companies that are invested in mRNA platforms are venturing into these and other new areas, addressing unmet needs.

A crucial lesson from the COVID-19 mRNA vaccines is the need for enhanced durability. Many companies are actively working on improving the duration of immune responses, aiming to provide extended protections beyond the currently observed 6–7 months. Additionally, while a potent medical tool in some region of the world, mRNA vaccines face logistical challenges in delivering these benefits to certain other geographical areas due to the requirement for a -60–80°C cold chain. Efforts are underway to improve stability, allowing mRNA to be stored in fridges for extended periods, ideally in pre-filled syringes. This will not only increase convenience but also broaden the reach of mRNA vaccines on a global basis.

In oncology, recent data from current mRNA therapeutic vaccine candidates has sparked new hope. Traditionally, cancer vaccines have faced challenges with many peptide vaccines failing to deliver significant benefits in Phase III studies. However, recent data, including those from randomized Phase II studies in early cancer settings like melanoma, have shown promise. Within the cancer setting, experiments with mRNA technology are increasing—specifically, exploring its use in combination with other immunotherapies to enhance treatment responses. However, the potential applications extend beyond vaccines, including encoding CAR-T and T cell receptors, tumor-suppressing factors, and antagonists to tumor-promoting factors.

Can you deeper on the current state-of-the-art in the application of cutting-edge mRNA technology with next-generation COVID-19, as you see it?

MM: It is evident from the data that mRNA vaccines have proven to be significantly more effective than other vaccine platforms and this was particularly highlighted during the COVID-19 pandemic. The mRNA platform showed the potential to deliver high efficacy, achieving levels of protection for around 90–95% of vaccine recipients—a figure rarely seen with the current standard, mainly peptide-based vaccine technologies.

Explaining why the mRNA platform surpasses peptide-based platforms is challenging, but in the context of a pandemic or other viral infections with continuous mutations, the mRNA platform allows for faster adaptation to emerging viral strains. This adaptability enhances patient protection and has a more substantial potential impact on the health system due to its flexibility.

The first-generation mRNA vaccines, although developed rapidly and demonstrating efficacy, revealed areas for improvement, such as durability and reactogenicity. The latter, while manageable, was a particular consideration. The second-generation mRNA backbone now focuses on addressing these gaps. At CureVac, our second-generation backbone has shown the ability to induce immunogenicity at very low doses, potentially improving tolerance. This advancement allows for the combination of different mRNA vaccines, such as for COVID and influenza, thus streamlining the vaccination process.

So, the ongoing evolution of mRNA vaccines aims to reduce dosages, enhance effectiveness, improve reactogenicity, and enable the combination of multiple viral antigens in a single vaccine. The technology’s potential extends to bacterial infections and parainfluenza, offering a unique advantage in creating comprehensive vaccines. Looking further ahead, efforts are concentrated on improving efficacy and tolerability, facilitating combinations of vaccines, and enhancing convenience through pre-filled syringes. This collective focus on formulation and backbone improvement aims to make vaccinations more accessible and convenient.

And moving to the therapeutic setting, as an oncology specialist, can you expand on what mRNA can bring to the cancer therapeutic armamentarium?

MM: As we have discussed, one significant approach involves using mRNA as a cancer vaccine, where it constructs and codes for cancer antigens, initiating an immune response in patients. This marks the starting point for us and others in the field. In parallel, we are exploring ways to augment the immune response by combining mRNA cancer vaccines with other immunotherapies such as checkpoint inhibitors, which are standard of care in most solid tumors.

In the cancer vaccine space, our exploration extends to both monotherapy and combination with data showing successful combinations of mRNA with CAR-T or adoptive T cell therapies. Combining mRNA with CAR-T cells has allowed for the in vivo expansion of CAR-T cells, addressing challenges related to yield and persistence.

In preclinical studies, we have observed that booster vaccines, administered approximately 6 months after CAR-T cell infusion, can re-expand the pool of CAR-T cells in vivo. This is particularly promising as it offers a potential solution to the challenges CAR-T cells face in both solid tumors and hematological cancers.

Beyond therapeutic vaccines, addressing the immunosuppressive tumor microenvironment is crucial. We are actively researching factors that can help overcome this suppression, exploring the possibility of encoding them alongside an mRNA vaccine. This dual strategy involves stimulating the immune system while mitigating immunosuppressive effects within the tumor.

Another exciting project that is explored in research is encoding T cell receptors using mRNA. This approach allows for the design of receptors based on known antigens, presenting a novel way to address cancer. While still in the theoretical stage, it highlights the versatility of the mRNA platform.

Lastly, optimizing mRNA technology for precise cell targeting remains a priority. This involves evolving the delivery mechanism to access cells that may be challenging for other therapies to reach. While we are still in the early stages, many are invested in this particular area or research.

What considerations and challenges do you see in incorporating mRNA technology into the cancer therapeutic space, whether in the combination therapy or monotherapy setting?

MM: Considering cancer vaccines, several challenges need to be addressed. The first is the identification of the right antigens or neoantigens for mRNA to encode because in the oncology space, a given patient may have hundreds of antigens. Sophisticated methodologies are essential to determine the antigens that elicit a robust immune response and are worthy of being encoded on the mRNA.

CureVac has taken a different approach by delving deeper into patient genome sequencing from tumor tissue, combining whole genome sequencing with mRNA sequencing to identify any possible genomic alteration in the patient’s tumor that could be immunogenic. By doing this, new classes of antigens and neoantigens that are not uncovered by conventional methods like UV4 exome sequencing can be discovered.

Another one of the challenges involves determining the future direction of cancer vaccines and deciding if they should be ‘off-the-shelf’ with shared antigens across different cancers, or personalized for each patient. CureVac is pursuing both approaches given the current uncertainty as to which might prove to be superior. Personalized cancer vaccines, while promising, face supply chain constraints and may not be applicable to patients with advanced disease due to the extended manufacturing turnaround times. The critical challenge there is to expedite and streamline this process—currently, sequencing, analysis, prioritization, and manufacturing may take up to 6 weeks.

The final challenge revolves around delivering the vaccine to the right cells in vivo. Current mRNA lipid nanoparticles reportedly reach only a small proportion of target cells—around 3–5%. As the goal is to target immune cells, it is vital to enhance the efficiency with which the right cells are reached, and to make sure this happens in sufficient quantities. This optimization is crucial for increasing antigen expression, subsequently boosting immunogenicity throughout the body where tumors are located.

What can we deduce from regulators’ reactions to mRNA technology applied in the therapeutic setting to date, and what should be some corresponding important points of focus for developers?

MM: In infectious diseases, following the success of the COVID-19 vaccines and given their well-characterized safety profile, regulators take a standard approach to mRNA vaccines. The emphasis lies on demonstrating various quality criteria for the manufacturing process. Clinical development follows a relatively standard path, requiring proof of immunogenicity, vaccine efficacy, and comparisons to existing products on the market. However, as the next generation of vaccines is developed, the focus has shifted towards areas not fully addressed during the pandemic, such as biodistribution and other features.

In oncology, on the other hand, mRNA-based therapeutics such as cancer vaccines fall under a different categorization, alongside gene therapies and cell therapies. This leads to more stringent regulatory requirements, and authorities tend to adopt a conservative stance due to the novelty of the technology. Generating substantial data with which to approach regulators becomes crucial, and a platform approach is employed to eliminate the need to repeatedly generate new information with each product redevelopment. This approach is intended to promote faster development programs in the future.

Development with mRNA cancer vaccines has slowed down recently due to the regulations. The goal is to continue working on refining the platform, leveraging the well-tolerated safety profile.

What is your vision for the future impact of mRNA on both prophylactic and therapeutic vaccine spaces?

MM: Looking to the future, the potential applications of mRNA technology are highly promising. With regard to prophylactic vaccines, there is hope for developing new vaccines against diseases that have been challenging to address, such as malaria and HIV, as well as in bacterial infections where traditional approaches, including antibiotics, have fallen short. The versatility of mRNA offers a glimpse into a future where we can address medical challenges and needs that were previously unmet.

In oncology, following the success of immunotherapies like checkpoint inhibitors in the last decade, I would say that mRNA is seen as the next significant advancement. Engaging the patient’s immune system is believed to be crucial for achieving long-term cancer control. While targeted therapies and chemotherapies have demonstrated effectiveness, they often provide transient benefits. The belief is that by instigating a robust immune response, mRNA-based cancer vaccines can play a transformative role in cancer therapy, particularly in earlier disease settings.

Further to this, I foresee increased research interest and activity in the use of mRNA technology to prevent cancer in individuals deemed to be at high risk based on genomic alterations in their germline DNA. This highlights the potential for mRNA to offer a comprehensive approach to addressing the complexities of this disease. In summary, the future holds enormous promise for mRNA to emerge as a powerful tool in areas where traditional medical approaches have faced challenges.

Lastly, can you sum up one or two key goals or priorities, both for your own work and for CureVac as a whole, over the foreseeable future?

MM: My personal goals are also corporate goals because they are closely aligned. My first goal is to move our vaccine programs forward, especially in influenza where we aim to transform the field. Currently, the influenza clinical development program is going smoothly, and I want us to continue towards generating better vaccines in both influenza and combination settings for the convenience of patients.

My second goal is to bring our cancer vaccine candidates into patients as soon as possible. We have great technology in the design space, so it is all about execution. The science is there, the technology is there—let’s execute it and get it into patients.

Biography

Myriam Mendila joined CureVac from Novartis, Switzerland, where she served as Chief Medical Officer in the Oncology Business Unit with responsibility for the worldwide medical affairs function. In this role, she was a member of several governance boards, including the Oncology Leadership Team, the Scientific Development Leadership Team, and the Development Committee Novartis. In the past, Myriam has held different leadership positions of increasing responsibility within global medical affairs, US medical affairs, global product development, and global product strategy at Roche/Genentech. Prior to that, she led Global Medical Affairs at Roche HQ in Basel. Myriam holds an MD from the Medical School Hanover. She has research papers in journals, including AIDS, The Lancet, The Journal of Clinical Oncology, Annals of Oncology, and The Lancet Oncology. 

Affiliation

Myriam Mendila PhD
Chief Development Officer,
CureVac

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Mendila M has stock/stock options in CureVac and Novartis.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & Copyright Information

Copyright: Published by Nucleic Acid Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2024 Mendila M. Published by Nucleic Acid Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Dec 7, 2023; Publication date: Jan 11, 2024.


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