September 1, 2024
Earlier this year, the RAND Corporation published a report commissioned by US Secretary of Defense Lloyd Austin, which details how current and future biotechnologies can be used as strategies against biological warfare (1). The report explains how state and nonstate actors have the ability to weaponize viruses to advance their own interests strategically, even if it impacts both allies and adversaries alike.
The report presents several realistic scenarios, including hypotheticals involving the Chinese and Russian governments using highly contagious airborne viruses to disrupt global stability and further their own aspirations to expand territories:
• The Chinese government might deploy a severe acute respiratory virus to disable US navy operations protecting Taiwan, resulting in military capture of the island in just 46 hours.
• Russia might use a novel, deadly airborne infection with a long asymptomatic contagious period to infect the United States and Western Europe with the goal of taking over former Soviet countries. Part of this strategy could be preparing an antidote in advance, leaving the region around Russia relatively unaffected with early access to a vaccine. As the United States and Western Europe contend with major disruptions to daily life and reduced supply chains, the Russian military would be able to annex former Soviet countries, disrupting international relations and the sovereignty of multiple nations.
To skeptics, such scenarios can seem extreme and apocalyptic. However, the RAND report makes a strong case for such threats that could be realized with synthetically generated, genomically targeted plagues leveraged as weapons. No vaccine would be available to mitigate the effects of unknown illnesses before they proliferate. Consider COVID-19: Its rapid spread showed the world that highly contagious, unknown viruses can halt daily life overnight and hinder organized operations of government, industry, and trade, destabilizing order on a global scale.
In response to the COVID-19 pandemic in 2020, the US government launched Operation Warp Speed, a project that demonstrated how messenger RNA (mRNA) and adjuvanted recombinant-protein vaccines could be developed within 100 days (2). Such vaccines also could be manufactured in large volumes, providing lifesaving protection during a pandemic. For viruses such as COVID-19 or influenza, slow production speeds and limited time to vaccinate significant portions of populations can allow for virus mutations that potentially lead to severe sickness or death. However, now that we have seen how the pandemic transpired, we understand that the program did not completely eradicate the threat of such a highly infectious virus. Based on the RAND report, a 100-day timeline for vaccine production would be too late to mitigate or prevent damage from biological warfare.
What if there was a simple solution that broadly protected populations against biologic warfare? Considering the many changing variables involved in protecting people against unseen biological enemies, a universal vaccine that covers both new and unknown strains of viruses would be beneficial. A universal vaccine could provide broad protection against ever-mutating viruses and facilitate production of new, targeted vaccines for lethal strains. In support of that approach, the US National Institutes of Health (NIH) highlighted the importance of further research into universal vaccines (3).
Scientists have been working for decades to find influenza-virus targets that are conserved across one or more virus families. Such targets are needed to provide functional protection against multiple strains and to decrease the chance of virus mutation. Research is being conducted on vaccine assets that attack viruses as a class of pathogens rather than specific strains or mutations.
My company, Longhorn Vaccines and Diagnostics, takes an approach to attack viruses at every stage of their life cycles: cell binding, replication, and exit (4). Our vaccines also induce both cellular and humoral immunity, a kitchen-sink approach that can attack continuously evolving viruses.
One challenge that many researchers face is constructing vaccines that both incorporate and attack multiple virus strains. Longhorn has developed and patented a composite peptide approach that enables vaccines to string epitopes together into unique peptides. We find conserved epitopes in each target, put them in an optimal order, and attach T-cell epitopes to stimulate the immune system further (5). We have partnered with the Walter Reed Army Institute of Research (WRAIR) to leverage its novel army liposome formulation (ALF) adjuvant containing a QS21 saponin (ALFQ). That adjuvant can induce balanced immune responses and reduce reactogenicity significantly (6).
Our composite peptides are manufactured synthetically and use linear epitopes produced in continuous amino acid sequences that elicit immune responses. The resulting antigens then can fight viruses. The vaccine can be delivered intramuscularly, but studies have shown that it also could be delivered effectively in intradermal and subcutaneous doses; Longhorn is studying those additional delivery mechanisms as well.
The linear vaccine approach is especially ideal for widespread protection against virus families. Such vaccines provide targeted immunity, which obviates targeting parts of a pathogen that could cause adverse effects or be less effective in stimulating immunity. Using composite peptides as a method for developing universal vaccines ensures immunity against an entire virus family with limited adverse side effects; that approach would be optimal given that virus mutations are inevitable by nature. The synthetic nature of composite peptides also makes the manufacturing process more straightforward and scalable than for vaccines that require whole pathogens or complex protein structures. Our composite vaccines have the potential for rapid and cost-effective development, which is especially crucial for potential their use in protection against emerging infectious diseases.
Additionally, we are developing passive immunization vaccines containing a cocktail of monoclonal antibodies (mAbs) to fight the bacterial infections that often lead to sepsis and tuberculosis. These cocktail formulations contain humanized extended-life antibodies that are predicted to have a six-month half-life and protect against multiple Gram-positive and Gram-negative bacteria, an improvement over current vaccines of this nature. This provides a comprehensive strategy for treating and preventing bacterial infections by neutralizing key toxins and enhancing bacterial clearance, which could improve patient outcomes significantly and reduce mortality. Additionally, we plan to deliver our mAb vaccines either subcutaneously or intravenously, depending on the population we are protecting. Further research is needed to establish the safety, efficacy, and optimal clinical application of this promising approach.
Universal vaccines for infectious diseases, whether based on peptides or mAbs, could be an answer to biowarfare. Longhorn’s work toward universal vaccines, in addition to its partnership with the US government, is one of many examples of collaborative research into protecting the world from another pandemic.
One of RAND’s long-term recommendations is to “encourage research on mitigation strategies for novel pathogen potentialities to anticipate and counter adversary biotechnology threats” (1). To effectively address the growing threat of novel pathogens and dangerous biotechnology, we must take comprehensive, proactive measures. Implementing mitigation strategies requires a multipronged approach, drawing inspiration from initiatives such as Operation Warp Speed. The US government successfully mobilized health agencies, boosted their collaboration with pharmaceutical companies, and eliminated burdensome red tape that otherwise would have slowed vaccine development.
First, we must establish a centralized task force to streamline and coordinate efforts across numerous health agencies, ensuring that all stakeholders work in unison. Substantial and sustained funding should be allocated toward biodefense and pandemic-preparedness programs, supporting both immediate response efforts and long-term research initiatives. Strengthening partnerships among government entities, pharmaceutical and biotechnology companies, and academic institutions can leverage the private sector’s innovation and expertise to accelerate the development of vaccines and therapeutics.
Additionally, regulatory reforms are necessary to expedite approval processes for vaccines and treatments, cutting through unnecessary red tape while maintaining safety and efficacy standards. Investments into advanced manufacturing technologies can enable rapid scale-up of vaccine production, ensuring quick distribution during outbreaks. And developing robust stockpiling and distribution mechanisms for essential medical supplies and vaccines is crucial for timely deployment.
Funding must be allocated to extensive research initiatives focused on developing broad-coverage vaccines. Identifying new viral targets through advanced research and establishing global research networks to facilitate data sharing will enhance our understanding and preparedness for biowarfare. Supporting innovative research in biotechnology and encouraging cross-disciplinary collaboration will drive innovation in stopping the spread of unknown infectious diseases. By taking the steps I have outlined, I believe that the United States can enhance its preparedness and resilience significantly against both natural and weaponized biological threats, helping to ensure robust national and global health security.
1 Matthews LJ, et al. Plagues, Cyborgs, and Supersoldiers: The Human Domain of War. RAND, 2 January 2024; https://www.rand.org/pubs/research_reports/RRA2520-1.html.
2 Operation Warp Speed: Accelerated COVID-19 Vaccine Development Status and Efforts To Address Manufacturing Challenges. US Government Accountability Office: Washington, DC, 11 February 2021; https://www.gao.gov/products/gao-21-319.
3 Reynolds S. Research in Context: Progress Toward Universal Vaccines. National Institutes of Health Research Matters, 25 July 2023; https://www.nih.gov/news-events/nih-research-matters/research-context-progress-toward-universal-vaccines.
4 Samji T. Influenza A: Understanding the Viral Life Cycle. Yale J. Biol. Med. 82(4) 2009: 153–159; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794490.
5 Kaumaya PT, et al. Peptide Vaccines Incorporating a “Promiscuous” T-Cell Epitope Bypass Certain Haplotype Restricted Immune Responses and Provide Broad Spectrum Immunogenicity. J. Mol. Recognit. 6(2) 1993: 81–94; https://doi.org/10.1002/jmr.300060206.
6 Rikhi N, et al. Unconjugated Multi-Epitope Peptides Adjuvanted with ALFQ Induce Durable and Broadly Reactive Antibodies to Human and Avian Influenza Viruses. Vaccines 11, 2023: 1468; https://doi.org/10.3390/vaccines11091468.
Jeff Fischer is the cofounder and president of Longhorn Vaccines and Diagnostics, 1747 Citadell Plaza #206, San Antonio, TX 78209; [email protected].
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