������ý

Vaccines Before Outbreaks? Jumpstarting Infection Prevention

COVID-19 mRNA (messenger ribonucleic acid) vaccines use a lipid nanoparticle to deliver mRNA encoding SARS-CoV-2 spike proteins to the cytoplasm of the cell.
Source: iStock When a new pathogen that infects humans is discovered, what’s the next step? The initial response may include a rush to develop vaccines and therapeutics, but even conducting this clinical research at an expedited rate can take months. With the omnipresent threat of undiscovered pathogens, scientists have been investigating methods to jumpstart vaccine and monoclonal antibody development before an outbreak occurs, shifting containment efforts from preventive to compulsory. But how does one arm themselves against a pathogen that has yet to be identified? Lessons learned during the COVID-19 pandemic may offer clues.

Lessons Learned from Building COVID-19 Vaccines

Is it possible to start building a vaccine without the complete genomic sequencing data for a pathogen? , M.D., Vice Chair of Medicine for Data Integrity and Analytics at Johns Hopkins School of Medicine, said a vaccine template is realistic within certain boundaries. Over the last few years, scientists have put this idea in motion.

Ray noted , Ph.D., an assistant professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health and a National Institutes of Health (NIH) investigator, and , Ph.D., a professor in the Departments of Medicine and ������ý, Biochemistry and Immunology at Morehouse School of Medicine and a former investigator for the National Institute of Allergy and Infectious Diseases (NIAID) and NIH. In studying the Middle East Respiratory Syndrome (MERS) coronavirus spike protein, Corbett, Graham and their colleagues ascertained—based on their knowledge of the way the spike proteins of coronaviruses bind and fuse—that a pre-fusion conformation might expose more neutralizing determinants than the native spike protein. The team endeavored to mutate 2 of the proteinogenic amino acids (prolines) that assist spike proteins in a pre-fusion conformation, exposing the binding surface for these 2 proteins. The result: better neutralizing titers in model systems.

In studying the Middle East Respiratory Syndrome (MERS) coronavirus spike protein, researchers accelerated the process for designing COVID-19 mRNA vaccines.
Source: Wikimedia Commons. , Corbett, Graham and their team were able to design a spike antigen with the 2 previously mutated prolines within 48 hours. “Based on their knowledge of beta coronaviruses, they were pretty confident that this would improve immunogenicity for protection,” Ray said. “That work was built before they had all the tools you would want to develop a vaccine antigen because they couldn’t empirically test this at the time they were designing it.” Pharmaceutical companies dedicated to rolling out a COVID-19 mRNA vaccine all committed to using the same spike protein sequence (all including the 2 proline changes) when developing the shot.

mRNA Vaccine Technology at Work

COVID-19 mRNA (messenger ribonucleic acid) vaccines use a lipid nanoparticle to deliver mRNA encoding SARS-CoV-2 spike proteins to the cytoplasm of the cell. “This was groundbreaking because there was a lot of hesitation about if the vaccine affects [the human host cell’s] DNA, when, in fact, it never enters the nucleus,” said , M.D., senior medical affairs manager at T2 Biosystems. Once the mRNA is released inside the cytoplasm, host ribosomes translate the encoded message to produce, package and express copies of SARS-CoV-2 spike protein. This, in turn, elicits an immune response and facilitates production of antibodies and T cells against the virus. “mRNA vaccines are the future,” Shah added. “For the most part, you’re going to have an immune response that is robust and can ward off potential disease.”

Beyond COVID-19, there is particular interest in mRNA technology for and mitigating the spread of other infectious diseases, like Zika virus, Ebola virus and tuberculosis.

The Future of mRNA Vaccines

Corbett and Graham’s team developed a model pathogen vaccine design years before the COVID-19 pandemic began. Could researchers do it again? Ray thinks it’s a possibility. “What Dr. Corbett and Dr. Graham have advocated for is a pandemic pathogen model antigen system, where they learn the biology of a type of pathogen—what it requires for entry or completion of its initial infection of a cell—and [then] design vaccine approaches around the critical steps in the entry program,” Ray said. “That’s a powerful approach when you know that there’s a good chance that a filovirus, coronavirus or other pathogen type will come out and be a problem.”

Could scientists make a vaccine without the protein sequence or structure? According to Ray, that may be less realistic, as this might entail binding to a host receptor rather than the pathogen. Here, there’s the risk of causing off-target effects because immune responses to the vaccine's contents could react to every cell that has the selected feature, not just the cells that are being attacked by a pathogen.

Starting Vaccine Development Before a Pathogen Spreads

Before a zoonotic virus begins to spread to humans, researchers can sequence viruses from animals and start to design pre-pandemic vaccine candidates. “You can look and say, ‘we know this type of virus family, and we can design proteins from those viruses and start testing them,’” said , Ph.D., an associate professor in the Department of Infectious Diseases at the University of Georgia. “It might not necessarily be plug-and-play, but we’re not starting from square 1.” He added that mRNA vaccine technology makes it possible to test multiple protein candidates at once, further accelerating the process of developing a vaccine.

In short, there are steps a researcher can take to develop a vaccine before a pathogen makes its way to human hosts. These include, but are not limited to:

1. Go Virus Hunting: Look for and sequence novel viruses in animal populations (e.g., coronaviruses and paramyxoviruses, which have a high risk of crossing over to humans).
2. Consider Feasibility: Investigate whether it’s possible to develop a vaccine candidate based on the genomic sequencing data.
3. Test Vaccine Candidates: With the sequence, test mRNA vaccines and see whether they elicit an immune response in an animal model.
4. Build a Database: Develop a bank of vaccine candidates. If a new virus emerges, determine whether a previously tested vaccine candidate (e.g., in mice) has a protein similar to the novel pathogen.
5. Make It Work: Begin modifying the vaccine candidate based on the genomic data from the new pathogen.

Sharing Data Catalyzes Vaccine Development

Data sharing can significantly increase the speed at which vaccines are developed and deployed.
Source: . COVID-19 vaccine development and rollout were directly dependent upon the speed at which genomic data from the pathogen was shared. However, sharing the sequence of a newly discovered pathogen before the data are published has not historically been the norm. “It is remarkable that the data were shared so freely, and we had a bunch of examples of people making these data visible to the world very rapidly,” Ray said. “If we try to imagine 2020, where researchers in China did not share genomic data so early, we would have seen bigger lags [in vaccine development]. I think we can argue that in the pace of a pandemic, a delay of 1 or 2 or 3 months would have [cost] many more lives.”

Ray added that there should be consideration for finding a way to continue this type of data-sharing to address other emerging and re-emerging pathogens, while, at the same time, honoring the individuals who share the data and recognizing the impact of their contributions. One suggestion is that the scientific community begin building a model pathogen library to store information for researchers around the world to tap into once a new virus makes an appearance.

Immunotherapy and Vaccines: The Dynamic Duo of Infection Prevention

Currently, Mousa’s lab investigates monoclonal antibodies and their applications for immunotherapies to combat infectious diseases. This involves extracting cells from an individual infected with a pathogen, , then mass-producing it in the lab.

Immunotherapy can be an excellent alternative to vaccines for patients who are immunocompromised and do not respond well to immunization (i.e., they might be given a prophylactic monoclonal antibody intravenously that will last a few months and can subsequently be delivered to the patient again), or for patients who are allergic to certain vital ingredients in a vaccine.

Additionally, immunotherapy can be coupled with vaccines for patients who may only be immunocompromised during a certain window of time. For example, Mousa said that patients who have cancer and are undergoing chemotherapy may use immunotherapy throughout the course of their treatment. Once the patient’s treatment is complete and their immune system is back to baseline, they could benefit from receiving a vaccine (i.e., they would then be able to generate an effective immune response). With this in mind, Mousa emphasized the importance of both immunotherapy and vaccines to keep patients safe and mitigate the spread of disease—one doesn’t necessarily replace the other.

“There’s lots of labs working to develop antibodies to viruses that do exist, but aren’t necessarily widespread,” Mousa explained. “Researchers are working to find patients [who have been infected], get blood samples and then generate antibodies against that virus. You could think about stockpiling those, so that if a particular virus does emerge [or re-emerge] at a larger scale, you’d already have an antibody stockpile and the capacity to generate it much faster.”

Improving Access to Vaccines Through Policy

Even if proactive steps are taken to ensure rapid vaccine development, public health officials must also consider how vaccines are distributed in order for them to effectively protect as many individuals as possible on a global scale. Prior to the identification of a pathogen, , M.Sc., Ph.D. Fellow, Lecturer in the Department of ������ý, Immunology and Parasitology at St. Paul’s Hospital Millennium Medical College, said public health officials can create infrastructure that will ensure that vaccines are accessible.

Almost . However, . “Equitable distribution is particularly important in the area of vaccines, which, if used correctly and equitably, could help to stop the acute phase of a pandemic and allow the rebuilding of our societies and economies,” Akalu said, noting the spike in funding for COVID-19 mitigation efforts and a recent desire to be proactive about preventing future pandemics.

To ensure that vaccines against emerging and re-emerging pathogens are accessible and equitably distributed, Akalu recommends focusing on 3 key areas when developing policies:

1. Support Production: An increase in vaccine production for infectious diseases will require consistent government support on a global scale to help countries expand their vaccine development and deployment capacities.
2. Bolster Trade: When scaling up vaccine production, streamlined vaccine supply chains will be critical.
3. Address Inequities: Akalu emphasized that market forces by themselves will not be enough to ensure successful vaccine deployment. He noted toward the Guyana COVID-19 Emergency Response Project, which not only supports equitable vaccine access, but also provides an example of the type of investment required in many under-resourced countries to facilitate better vaccine distribution. “Market forces alone will not suffice to ensure accessibility in vaccine deployment; we must also support policies that establish production equity,” Akalu emphasized.

---

ASM's Global Public Health Programs (GPHP) equip countries to surveil and respond to infectious diseases.