Stacy R. Lindborg, President and Chief Executive Officer of IMUNON, discusses why research is needed to inform better strategies for infectious diseases such as Covid-19 and a new, multivalent non-viral DNA approach to vaccine development that has the potential to address continued unmet needs in the field. 

Vaccines have long been a cornerstone in combating a wide range of infectious diseases, yet of more than 80 pathogenic viruses discovered since 1980, fewer than 4% have a commercially available prophylactic vaccine. Five years after the Covid-19 global emergency declaration, the need for rapid and scalable vaccine development has never been clearer, especially as new pathogenic threats continue to emerge. 

However, as with traditional drug development, designing safe and effective vaccines comes with its challenges, such as the need to target the optimal viral proteins or antigens to elicit strong immune responses. At the commercial level, hurdles remain related to manufacturing and scale-up for mass production and ensuring timely and equitable distribution across communities and geographies. The messenger RNA (mRNA) technologies used to develop Covid-19 vaccines with the urgency required at the height of the pandemic was a massive step forward. But as evidenced by new variants in the past several months, such as NB.1.8.1, LP.8.1, and XFG, it is critical that we build on prior successes by developing and introducing new vaccine technologies to address the continued unmet needs in this evolving field. 

Learning from the success of mRNA vaccines 

There are generally two primary categories of vaccines: inactivated and live-attenuated vaccines. As the name implies, inactivated vaccines use inactivated forms of a pathogen to train the body to trigger an antibody response that will be able to create what is known as immune memory – the ability to recognise and effectively fight future infections. Scientists culture large batches of a pathogen and then use heat or chemicals, such as formaldehyde in most cases, to inactivate or kill a pathogen so that it can be used antigenically, or as an antigen source. Some examples of inactivated vaccines include the modern flu vaccines and the polio vaccines. In live-attenuated vaccines, weakened forms of a pathogen are used, allowing the body’s immune system to recognise the pathogen without causing severe illness, more closely resembling a natural infection. Live-attenuated vaccines include the MMR (measles, mumps and rubella) and chicken pox vaccines. 

While these traditional vaccine technologies have saved countless lives, they present several limitations, such as their reliance on pathogen (viral or bacterial) replication, which often hinders manufacturing speed. Other approaches, such as subunit, conjugate, and recombinant vaccines, may also face challenges due to the slower pace of microbial and cellular processes involved in their development and production. Vaccines based on inactivated viruses, attenuated viruses, or antigen subunits primarily induce a humoral immune response but are poor activators of the cellular immune response, which is essential for eliminating pathogens already inside host cells. 

The Covid-19 pandemic taught us that speed is paramount when responding to emerging pandemics and epidemics. The emergence of mRNA vaccines liberated manufacturing from traditional microbial constraints, enabling the rapid production of millions of doses and allowing swift adaptation to new viral strains and mutations, among other advantages. 

The Covid-19 mRNA vaccines were significant scientific breakthroughs that have conceivably saved millions of lives, eased the infectious disease burden on healthcare systems, and revitalised the world’s ability to socialise and connect. The story of their success should not create complacency but rather teach us the value of continuing to push for new and innovative vaccine technologies with improved function, durability, and storage stability. Building on this strong foundation and advancing beyond existing mRNA technologies to meet the evolving needs of future pathogens will be essential in the years ahead. 

Taking a multivalent, non-viral DNA approach to vaccines  

One of the limitations of mRNA vaccine technologies is that they are built upon an inherently unstable molecule. mRNA generated within cells is evolutionarily designed to degrade quickly over time. While manufactured mRNA can be modified to enhance stability (synthetic 5’ cap, polyA tails, and more), the base nature of mRNA molecules remains the same. As a result, proteins encoded by mRNA vaccines are expressed for short periods of time, limiting the window of immune system exposure and response. 

As we learned during the height of the Covid-19 pandemic, mRNA vaccines are also temperature-sensitive, requiring ultra-cold storage during production and transportation, which can significantly increase distribution costs. In addition, the limited availability of cold storage in developing regions and countries can make it difficult to achieve equitable access to mRNA vaccines during a global pandemic. mRNA vaccines are also associated with inflammation, reactogenicity and organ toxicity attributed to the presence of the lipid nanoparticle (LNP) delivery system or double stranded mRNA. 

But what if researchers were able to teach the body to elicit an immune response that protected against infectious diseases such as Covid-19 without needing a virus, device, or other access barrier to deliver the vaccine? 

A new technology platform, called PlaCCine, has been engineered to develop nucleic acid vaccines for Covid-19 and address the logistical challenges often associated with mRNA vaccines. The PlaCCine platform uses a non-viral delivery vector to promote the delivery of plasmid DNA into cells, which has been shown to have promising results in preclinical studies. Published literature1 also shows this approach offers a more durable expression profile, resulting in longer-lasting antigen expression compared to mRNA. This prolonged antigen presentation givesthe immune system more time to interact with viral and bacterial molecules, improving the likelihood of generating strong immunity that can potentially last a long time. Unlike mRNA vaccines, the vaccines developed based on the PlaCCine platform are generally stable for up to one year at 4°C and up to two months at room temperature, helping to streamline and improve the logistics of shipping and distribution worldwide.

Another known limitation of mRNA technology is its constrained coding capacity, which makes multivalent vaccine design more difficult. Multivalent vaccines are designed to immunise individuals against multiple strains of a virus or bacteria with a single inoculation (compared to standard monovalent vaccines, which only protect against a single strain). While bivalent mRNA vaccines2 have been developed and approved for use, mRNA often has less coding space than plasmid DNA. Plasmid DNA is a more flexible medium, which allows researchers to encode multiple antigens from one or different pathogens in a single vector. Multivalent vaccines can confer broader protection against circulating strains of viruses and can even help provide protection against future strains of a pathogen that have yet to emerge. 

Recently, this next-generation, multivalent DNA vaccine platform was used to develop a vaccine targeting the SARS-CoV-2 Omicron XBB1.5 variant. Results from3 a Phase 1 proof-of-concept study demonstrated the vaccine’s durability of protection at six months after a single dose and up to a 3-fold median increase in the serum neutralising antibody (NAb) titers from baseline at six months. The vaccine was generally safe and well tolerated with no serious adverse events among study participants reported. In the same study, data showed an immune response in participants against the XBB1.5 variant and many newer variants following treatment, including JN.1, KP.2, KP.3, KP3.1.1 and L.B.1, indicating the vaccine’s cross-reactivity and suggesting broad-spectrum protection. Modest increases in T-cell responses were observed in trial participants who received multiple immunisations or had Covid-19 infection prior to the study. 

Together preclinical and clinical studies to-date have shown proof of immunogenicity and early indications of durability of protection, and stability at workable temperature suggesting that next-generation vaccine technologies may offer practical, durable alternatives to the already successful mRNA vaccines. A multivalent, non-viral DNA approach may provide the versatility and resilience needed in vaccine design to address potential future rising pathogens. 

Looking ahead – investing in vaccine stability  

Beyond Covid-19, high-priority pathogens with unmet needs could include influenza, respiratory syncytial virus, HIV, Ebola, cytomegalovirus (CMV), and emerging threats such as dengue or Zika – viruses where vaccines are either absent, suboptimal, or hard to distribute due to stability issues.  

There will always be a strong demand for a variety of vaccine strategies, as each pathogen presents unique challenges for eliciting a strong immune response. PlaCCine vaccines are DNA-based vaccines that do not require a virus or device and offer another tool in the toolbelt and present several advantages to other vaccines approaches.  

By investing in next-generation vaccine technologies now, we are paving the way to meet tomorrow’s infectious disease threats with greater speed, resilience, and equity. 

References

1: https://pmc.ncbi.nlm.nih.gov/articles/PMC4292072/

2: https://www.nature.com/articles/s41541-025-01062-8

3: https://investors.imunon.com/news-releases/news-release-details/imunon-announces-six-month-data-showing-durability-protection

About the author

Stacy R. Lindborg, Ph.D., was appointed president and chief executive officer of IMUNON, Inc. in May 2024. She has served on the company’s board of directors since June 2021. Dr. Lindborg has nearly 30 years of pharmaceutical and biotechnology industry experience with a particular focus on R&D, regulatory affairs, executive management and strategy development. She has designed, hired and led global teams, guiding long-term vision for growth through analytics and stimulating innovative development platforms to increase productivity.