Intramuscular vaccines have been at the center of attention during the COVID-19 pandemic, saving millions of lives and showing great efficacy in preventing severe infections and lengthy ICU stays. However, challenges such as high distribution costs, limited storage capabilities, and skepticism toward traditional vaccine treatments have made it difficult to increase vaccination rates throughout the world. In response, BlueWillow Biologics has been focusing its research and development on mucosal vaccines for COVID-19. Such vaccines could be a solution to these challenges because they are easy to administer, minimize systemic side effects, and potentially prevent virus infections of asymptomatic cases through inducing mucosal immunity, the body’s first line of defense. In this Q&A with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., BlueWillow Biologics Chief Executive Officer Chad Costley, M.D., discusses the historical development of mucosal and specifically intranasal vaccines, their advantages compared with intramuscular delivery, and what the future holds for the vaccine space and BlueWillow in particular.

David Alvaro (DA): In terms of global equity, what do you view as the limitations of intramuscular vaccines for COVID-19 and for other diseases?

Chad Costley (CC): The lack of mucosal immunity and limited durability of immunity. As the recent variant surges have highlighted, preventing infection and spread is different than preventing disease. Intramuscular vaccines have performed well in terms of preventing severe disease, but without vaccines that prevent infection by providing immunity at the point of pathogen entry –– the mucosa –– we are going to continue to see persistence of infection and its spread. In addition, we need more affordable vaccines, as approximately one-third of the world has still not received any COVID-19 vaccination, and the cost, supply chain requirements, and injection administration challenges of the current vaccines present real obstacles to closing that gap.

DA: To what extent do you think that the resistance some people have to the vaccine in the United States and Europe relates to the fact that it’s an intramuscular injection?

CC: I’m a primary care physician by training and have seen firsthand that a lot of vaccine hesitancy stems from people not wanting to get poked in the arm. We have people pass out even before the needle is taken out of the sleeve, because they’ve been thinking about it for days. I think some of the conversation surrounding this topic has ignored the fact that there’s an underlying aversion to injections, regardless of views about vaccines themselves.

DA: What other administration options have been explored?

CC: Mucosal vaccines broadly have a lot of potential, as a vaccine delivered across the mucosal surface can specifically elicit mucosal immunity. There are three main routes through which mucosal vaccines could be delivered: oral, inhalation, and intranasal, which is what BlueWillow and others are developing. These technologies explore the idea that there’s a duality to our immune system: systemic immunity, which is primarily what we elicit when we inject an intramuscular vaccination; and mucosal immunity, which we believe better simulates what happens when you actually get an infection. The vast number of infectious diseases, whether they be viral or bacterial, start on a mucosal surface. If you deliver a vaccine to a mucosal surface — whether that is in the nose, the lungs, or the gut — you’re better simulating the immune reaction that you get from an infection and thus activating both parts of the immune system, and particularly stimulating mucosal immunity in a way that systemic vaccination doesn’t.

DA: What is the benefit of that mucosal immune response?

CC: Intuitively, the best way to deliver a vaccine is to use the approach that best mimics how the infection starts. If you were targeting an intestinal infection, it might make sense to use an oral vaccine, potentially more so than an intranasal vaccine — for this reason, none of the vaccines in our intranasal pipeline target intestinal infections.

Respiratory diseases, like COVID-19, generally start in the nose and upper respiratory tract. We want to induce immunity starting at the point where the infection would occur. By delivering the vaccine directly to the mucosa rather than systemically, we can potentially both increase the benefits and decrease side effects. With the right formulation and a safe intranasal delivery system — which we have — you limit the need to elicit such high antibody response in the serum to induce protection. A robust antibody response to an mRNA vaccine elicits significant systemic responses, such as fever and aches. These vaccines are safe, but I personally spent the day on the couch after my booster. We believe that intranasal vaccines can decrease not just systemic side effects but also local ones. Any time you take a needle and pierce through the skin, there’s some risk of infection and local inflammation.

DA: What has been the history of the development of intranasal vaccines to date?

CC: Intranasal vaccines have been a target for development for a very long time but have faced headwinds because of some early safety setbacks. Early on, there was an intranasal vaccine for flu in development that went into human studies in Europe, but unfortunately the adjuvant, which was a derivative of the cholera toxin, crossed the blood–brain barrier and caused some significant central nervous system side effects, including Bell’s palsy.

As a result, when we talk to anybody about our technology, we are typically faced with the same questions: Can you spray a vaccine into the nose intranasally safely with an adjuvant? Or do you have to go with a nonadjuvanted approach, using adenovirus vectors or pure antigen-delivery vectors? The problem with those is that they often don’t elicit a robust immune response. So, you end up with this dichotomy in the historical perception: if you use an adjuvant, you’re dancing close to or crossing the safety line, but if you don’t, you don’t end up eliciting a very robust immune response and thus have a vaccine with low efficacy. This dogma that adjuvants in the nose are unsafe has cost intranasal vaccines many years of support and investment and has really slowed development.

At BlueWillow Biologics, we’ve developed an intranasal adjuvant that has been shown to be safe in humans. This enables us to get that robust mucosal and systemic immune response while not crossing the blood–brain barrier and causing CNS toxicity. In fact, we don’t cause any serious adverse events. This isn’t just theoretical and animal work observation; we have data from over 400 humans now.

DA: Can you discuss the origins of the NanoVax platform and the genesis of BlueWillow?

CC: NanoVax is a broad intellectual property platform combining patents owned by the University of Michigan and exclusively licensed to BlueWillow, as well as intellectual property that BlueWillow developed on its own and patented. Our nanoemulsion technology was invented at the University of Michigan, initially for antimicrobial dermal applications, as it has inherent antimicrobial quality. The company was initially focused on dermatologic applications, with early work on a topical treatment for cold sores. Later, it was discovered that these emulsions also efficiently deliver antigens and adjuvant the immune response through a different mechanism of action when used in intranasal vaccines.

The way in which we’ve been funded is also pretty unique. Most biotechnology companies have had significant institutional funding at this juncture. Early on, there was a venture capital investment for the dermatology programs, but for vaccines, we’ve never taken a large investment from an institutional investor. We’ve made it to the clinical stage with relatively limited funding compared with other biotechnology companies. We are very thankful to our government and nongovernmental partners who’ve helped us thus far, but clinical-stage development for the multiple programs in our pipeline is very expensive. So, we’re really at an inflection point for the company to get these intranasal vaccines all the way to the finish line. We look forward to propelling these vaccines to benefit millions of people by engaging in extensive collaborations, whether that means more institutional investors or strategic partnerships with larger pharmaceutical and biotechnology companies.

DA: Are you exploring licensing the technology for pharma partners?

CC: We’re actively pursuing strategic partners for licensing and technology advancements. We want this technology to benefit millions of people, and the concept that we’ve been able to prove out in preclinical and early clinical work really enables a larger partner to come in and rapidly get this to market. As a clinician by training, I know that there are real people out there whose lives would really be helped by our technology. I wake up every morning thinking: the patients out there are waiting, so let’s get this technology advanced as rapidly as we can.

We want people to run with this technology, and we’re very open to those discussions. An intranasal adjuvant that’s demonstrated safety in humans — that’s a big deal. That seems like a very simple statement, but there just aren’t other technologies out there like this. While there are other intranasal companies doing great work, most of them use a viral vector delivery approach, which has significant limitations. Our combination of a strong adjuvant with parallel efficient antigen delivery is what makes BlueWillow so unique.

DA: Thus far, we’ve mostly discussed intranasal vaccines for respiratory diseases, which is pretty intuitive. The herpes pipeline candidate is maybe less obvious. Can you discuss that connection?

CC: Sexually transmitted herpes is also a mucosal infection, so developing a mucosal vaccine again makes intuitive sense. There is significant cross-talk in the mucosal immune system, meaning immunity elicited in one mucosal area, such as the nose, propagates to others such as the genital tract. This isn’t just theory; we have very compelling evidence in the primary animal model for herpes that our intranasal vaccine protects from vaginal herpes outbreaks and decreases virus carriage. This latter outcome is critical, as the majority of herpes infections result from exposure to someone who is asymptomatic. There have been some advanced intramuscular vaccine candidates from big companies that ended up with disappointing results in advanced clinical trials. We hypothesize that you can’t get sufficient protection against outbreaks of this mucosal disease purely by eliciting a strong antibody response in the blood; you need mucosal immunity.

DA: How challenging is it to convince government funding sources of the value of this approach?

CC: Any paradigm shift can be hard for big institutions to embrace. Most vaccines currently available are intramuscular. People have seen the value and promise of intranasal vaccines for a long time, but early technological challenges created skepticism. One of the lessons from the COVID-19 pandemic must be the need to take a hard look back at our vaccine paradigms and see how we can challenge them and do things differently.

We have support from government agencies, but, to be frank, we need more. Operation Warp Speed got a first generation of vaccines for COVID-19 out there, but the second-generation vaccines have not been as well funded as I believe they should be. There’s always hesitancy to move to the next phase, and things tend to change more slowly than those of us who are trying to change them would like. I think a lot of early-stage vaccine development companies find themselves in that situation now.

DA: There have been recent, well-publicized issues with manufacturing and capacity crunches in fill/finish for vaccines. Does the manufacturing process for intranasal vaccines sidestep some of those bottlenecks?

CC: Yes. Manufacturing of the adjuvant, while scientifically elegant, is easily scalable and inexpensive. Our vaccines are formulated through simple mixing of the adjuvant and the antigen. It’s a straightforward and efficient process.

There’s also the potential to develop a multiple-dose sprayer, where you’re simply sterilizing the tip and administering at very low cost to multiple people. That makes this method very inexpensive, since the whole concept of multiple doses becomes much more feasible for an intranasal spray than it would be for an intramuscular injection.

Another big advantage is self-administration. We use an Aptar device, which nebulizes the compound and sprays it into the nose. Storage is also much simpler. Neither the nanoemulsion nor the vaccine formulations require super-cold temperatures (like what you need for mRNA), only refrigeration.

DA: Are there specific use cases where it would still make more sense to use intramuscular delivery?

CC: I think the biggest argument is the established paradigm of intramuscular treatments. We know how to develop them, and we know how to measure them. You’ve got correlative protection where, if you get certain antibody responses in non-challenge studies, you can predict protection. That’s more difficult with intranasal vaccines, because measuring IgA or IgG in the nose is more challenging than measuring it in the blood, although the reliability of the assays is improving. In terms of specific diseases where intramuscular administration makes more sense, I can’t think of one, and that may reflect our focus on diseases with a strong mucosal component. But any case where a very strong, immediate, systemic antibody response is the preferred route of protection would be an argument for an intramuscular approach. Intranasal vaccination stimulates systemic immunity, but antibody responses in the bloodstream are higher after an intramuscular injection than an intranasal spray, which is not surprising. However, that doesn’t mean that they protect better, just that they make more serum antibodies.

DA: Do you see intranasal eventually becoming the dominant route for vaccines?

CC: It’s a heady goal for a small company, but yes. I think it’s more intuitive to mimic the infection. If the infection starts in the gut, have a vaccine that starts in the gut. If the infection starts in the nose, have a vaccine that starts in the nose. Intramuscular became the dominant paradigm because of early technological advances — it creates systemic antibodies that are easy to measure, and you can establish correlates of protection. Millions of people have been saved by that approach, but there are reasons to do it another way. I hope that I wake up someday in my retirement and can look back and say that BlueWillow had a small part in that paradigm shift, because we think it would be much more beneficial for humanity than the current approach.

DA: Are there any major milestones ahead for the company?

CC: We’ve published interim data and soon will release a final report on our recent phase I clinical trial in anthrax in humans, which further establishes the safety of the adjuvant. We would very much like to have governmental or nongovernmental support for what we think is a critically important trial that should be conducted right now exploring boosting previously intramuscular vaccinated COVID-19 patients with an intranasal booster to elicit mucosal immunity. This would not only protect them from disease but will address the issue of viral carriage in asymptomatic patients, which is a significant contributor to the virus spread — a lot of us are still carrying the virus around despite not feeling sick, which contributes to the emergence of variants. An approach that looks at intramuscular and intranasal treatments as complimentary could be a game-changer.

DA: Is there anything you’d like to share about the team at BlueWillow, the different types of expertise you’ve assembled, or the future of the company?

CC: I’m humbled by the intelligence and dedication of the people I work with. It’s amazing to watch these people get up in the morning and work so diligently — in some cases with less funding than they would have at a Big Pharma company — and yet make extraordinary scientific advances. We’ve assembled a team of people who not only have deep scientific expertise but share that passion for the patients who are waiting.

The future of BlueWillow is ultimately difficult to predict. Small biotech companies typically get acquired and/or license their technology to larger companies that can more rapidly advance the science, but some do grow organically into larger, publicly traded biotech companies. I hope that, 5–10 years from now, we are through clinical development for at least a couple of products that are used as an intranasal vaccination or immunotherapy by millions of people. The BlueWillow name being in the background or in the forefront of that is a lot less important to me than the fact that the technology will be in the market helping people.