The Changing Faces of Vaccines: Innovations and Future Trends in Vaccinology

Vaccines are, without question, one of the most important and effective developments in the history of public health. Since 1974, vaccination has averted an estimated 154 million deaths and resulted in the gain of 10.2 billion health years.¹ Both long-established vaccine strategies – such as attenuation, inactivation and pathogen subunits – and newer technologies (e.g., mRNA), are able to provide protection against a wide variety of pathogens and diseases. However, despite these successes, substantial disease burdens still persist around the world, as do challenges to novel vaccine development and deployment. Subsequently, vaccine research must adapt to see further successes.

As public health advances and successful vaccine development has brought many infectious diseases – particularly in high-income countries – under control, interest in novel vaccines has shifted. Non-communicable and chronic diseases such as heart disease and dementia are now prime targets for novel vaccines, bringing new challenges and requiring novel approaches. In addition, while the COVID-19 pandemic showed that rapid, effective vaccine responses to emerging diseases are possible, the instability and complex delivery requirements of many vaccine platforms can complicate deployment. This leads to geographical vaccine inequity and preventable disease burden in low-to-middle income countries (LMIC) and remote areas, significant roadblocks to global public health.

Vaccines for chronic diseases

Throughout their history, vaccines have been targeted at infectious diseases. However, with 7 out of the 10 leading causes of death now noncommunicable diseases, vaccines for noncommunicable and chronic diseases are now gaining traction.² This can pose novel challenges for researchers, as these vaccines must often target self-antigens and may not be compatible with existing vaccine platforms.

One platform that shows promise for preventing chronic diseases, however, is virus-like particles (VLPs). VLPs are formed by overexpressing the genes for viral structural proteins in an expression system. These proteins then self-assemble into empty particles that mimic the size and pattern of the original virus – without the viral genome, or the potential to cause disease. VLP vaccines are already used to protect against human papillomavirus (HPV) and hepatitis B and E viruses but also show promise against chronic illness. This is currently being investigated by Professor Bryce Chackerian at the University of New Mexico to develop vaccines against chronic issues such as high cholesterol, Alzheimer’s and even drug addiction.

“VLPs can be used as vaccines for the viruses they’re derived from, but we can also use them as a platform to display other antigens,” said Chackerian. “VLPs have these highly dense, repetitive structures that can interact multivalently with B cell receptors and lead to extremely durable immune responses of a stronger magnitude. It’s this durability that makes the VLP-based approach potentially really useful for chronic diseases.” Additionally, the foreign viral antigens in a VLP induce a T helper cell response, which is key in breaking tolerance and initiating an immune response against a self-antigen.^{3, 4}  Indeed, a lot of autoimmune diseases often appear to be triggered by viral infections.⁵

Chackerian’s group uses information on monoclonal antibody (mAb) development as a guide for selecting potential targets for vaccines. “If clinical trial data or US Food and Drug Administration approvals show that a mAb-based drug against a chronic disease target is safe, that suggests that a vaccine-based approach against that same target could also be safe,” he explained. “That’s something we really worry about, because you can withdraw a drug if there is an adverse event, but you can’t just turn off the immune response to a vaccine.”

A good example of this approach is a vaccine that Chackerian is working on against a molecule called PCSK9, which, when blocked, can reduce LDL cholesterol levels.⁶  mAbs targeting PCSK9 are safe and approved, and now a VLP vaccine could elicit the same effect – but with distinct advantages over a mAb therapy. “mAbs are generally very, very expensive and difficult to produce, while VLP vaccines aren’t.  mAbs are also more likely to induce side effects such as infusion reactions than vaccines,” Chackerian said. “For long-lasting chronic diseases, we may need a booster vaccination every 6–12 months, but this is still less frequent than a mAb therapy, which improves patient uptake.”

Chackerian is most optimistic about his lab’s potential Alzheimer’s disease vaccine. The VLP vaccine targets tau, a structural protein in the brain that, when hyperphosphorylated, is secreted out of cells and begins to aggregate and cause the tangles – and subsequent symptoms – associated with Alzheimer’s disease.⁷ “We’re trying to target the pathogenic form of tau, specifically at the sites that get phosphorylated, rather than the normal form,” he explained. “The aim is to delay or even halt disease progression. It’s been very promising in animal studies, and we’re aiming to start the process to begin clinical trials in about a year. Getting a vaccine for Alzheimer’s would be very exciting, but the bigger goal would be to make it globally accessible, and I think vaccines have better potential for that than, say, mAb therapies.”

Improving vaccine equity

Making vaccines more globally accessible is an essential factor in vaccine innovation, and one that cannot be ignored. Nowhere was this more obvious than during the COVID-19 pandemic, where vaccine inequity – compounded in part by the ultra-low temperature demands of the mRNA vaccines – resulted in less than 10% vaccine coverage in the first 12 months of global vaccine distribution in LMICs, compared to 75-80% in high-income countries, resulting in preventable deaths and disabilities.⁸

One of the main challenges in equitable vaccine development and deployment is the inherent instability of many vaccine platforms. “Vaccines consist of complex biological molecules and particles, which are easily damaged by high temperatures, freezing, light, agitation or other external stress factors. Some of the newer vaccine technologies, like mRNA-based vaccines, are especially sensitive to heat,” said Dr. Renske Hesselink, director of manufacturing and supply chain innovations at the Coalition for Epidemic Preparedness Innovations (CEPI). Her work focuses on the 100 Days Mission – a goal to develop vaccines within 100 days of identification of a new viral outbreak with pandemic potential, aiming to contain outbreaks faster and target vaccines to those who need them most.

Key to the success of the 100 Days Mission is the advancement of innovations in vaccine storage and stability. Currently, maintenance of the cold chain – the transport and storage of vaccines at low (2–8 ^oC) or ultra-low (-80 ^oC) temperatures is essential for preserving vaccine safety and effectiveness.⁹ “While advantageous for maintaining vaccine potency, such temperature requirements can make vaccines inaccessible to remote areas or low-resource settings,” explained Hesselink. Cold chain requirements can also result in huge amounts of wastage, as vaccines must be discarded if they have not been kept at the correct temperature, or if they remain unused at the end of their limited shelf life.¹⁰

Creating thermostable vaccines is all very well, but proving a novel vaccine’s stability takes time – time that may not be available during an outbreak scenario. Therefore, Hesselink’s work also investigates stability modelling. In this method, vaccine degradation is measured at multiple temperatures for a relatively short period of time (e.g., two months), then mathematical modelling is used to predict long-term stability.¹¹ “[This method] is currently being tested for various vaccine platforms, such as RNA-based vaccines and protein-based vaccines. This gives us confidence that we can apply the methodology when we need it in a rapid response situation,” said Hesselink. “An important part of this work is alignment with regulatory authorities, to ensure we generate the data they need to confidently approve shelf life based on platform data and predictive stability modelling.”

Novel delivery systems

“In support of CEPI's equitable access mission, we're really looking to see a step change in the way that some of these vaccines can be stored and delivered – to provide hope and protection to communities worldwide, while also minimizing potential wastage,” said Hesselink. There are several approaches being used at CEPI to achieve this goal, one of which is dried vaccine formulations. “Removing water from the product often halts or slows down degradation processes, similar to freeze-drying of food, for example,” she explains. “This also provides opportunities in alternative deliveries, such as microarray patch, solid-dose, intranasal dried powder and sublingual thin film vaccines.”

Developing alternative delivery systems for thermostable vaccines is also an opportunity to solve another of the key challenges facing vaccine development: the need for repeated booster shots. Most current vaccines are delivered intramuscularly by hypodermic needle, and most require more than one dosage to achieve protective immunity. In addition to effective cold chain storage, this requires a skilled operator, appropriate sharps disposal and does not encourage patient compliance due to pain and phobias. Dr. Thanh Duc Nguyen, associate professor in the Department of Mechanical Engineering at the University of Connecticut, is developing an alternative microneedle delivery system to tackle this issue.

“Microneedles are tiny needle tips, only 400–600 micrometers long,” said Nguyen. “When we create arrays of these microneedles on patches that can be applied to the skin, the needles penetrate the superficial dermal layers of the skin, shallow enough that they avoid nerve endings and don’t cause the pain usually associated with hypodermic needles.” However, this doesn’t mean that they can’t reach the immune system. “These layers of the skin contain a lot of immune cells, such as Langerhans cells, that can trigger the immune response in a much more effective manner than a traditional hypodermic injection,” he explained. In the dermal layers of skin, specialized antigen-presenting cells such as Langerhans cells and dermal dendritic cells take up vaccine antigens, then travel to skin-draining lymph nodes to activate an immune cascade that initiates both the humoral and cell-mediated arms of the adaptive immune response, establishing an extensive immune response and increasing vaccine efficacy.¹²

Combining microneedle patches with a dried vaccine formulation could create a robust, thermostable vaccine that is more easily deployed, transported and administered, even in remote areas with limited cold chain or health infrastructure. “We add an excipient, similar to a sugar, which binds to the vaccine antigen, immobilizes it and prevents it from undergoing any conformational changes when it’s dried, that might prevent the immune system from recognizing it,” says Nguyen. “These dried vaccines are then very stable for long periods of time and very compatible with microneedle patches.”

Conclusion

There is no doubt that the field of vaccination is changing. With greater demand for vaccines against novel targets – both chronic diseases and emerging threats – and the essential need for global equitable access, future vaccines may look very different from the platforms and delivery systems we are familiar with. Chronic diseases such as heart disease and Alzheimer’s are a worldwide issue, and VLP vaccines could be a safe, simple way to protect against them. The ability to make these vaccines – and those for infectious diseases – thermostable could be revolutionary.

“If we can successfully scale up the manufacturing of the microneedle patches,” said Nguyen, “it could be game-changing for the way we vaccinate people, and eventually the way that we administer drugs.” Hesselink agreed: “I think it is a very exciting time for this field. We have been using syringes and needles for more than a century to vaccinate people, but they do have certain drawbacks. Novel technologies are now on the brink of improving that, making vaccines more equitably accessible to people around the world, in an easy, safe, pain-free manner.”