Vaccines are a critical tool to prevent infectious diseases and improve global health. Safe and efficacious vaccination has saved millions of lives, increasing the average life expectancy from 40 years in 1900 to more than 80 years today.
Over time, the way that vaccines are developed has changed. Improved understanding of the immune system and the availability of advanced structural biology tools and genetic delivery systems have unlocked innovative concepts to vaccine design. The various vaccines developed for COVID-19 presents a great example of how innovation can transform the area of vaccinology.
This article covers the challenges associated with conventional vaccine approaches and elaborates on some of the recent innovations which can help design better vaccines.
What are the challenges with conventional approaches?
Vaccines have traditionally been developed using the disease-causing pathogen in different forms – live, attenuated and at times killed or inactivated viruses. Newer vaccines are developed using recombinant technology and include conjugate vaccines, subunit vaccines and virus-like particles.
Virus-based vaccines can trigger a strong immune response, but there are some challenges that may restrict their use. Live-attenuated vaccines pose the risk of reversion to the pathogenic form, while inactivated vaccines may not be able to mount an adequate immune response. Subunit vaccines were designed to counter these challenges, but these vaccines may also trigger an insufficient immune response, inducing partial protection in most cases. Another point to consider with traditional virus-based vaccines and subunit vaccines is their long development timelines, which make them less useful in rapid response strategies such as pandemics.
How can we meet the new challenges of vaccine development?
Several promising vaccine technologies and novel strategies have been developed and many are being evaluated to meet the challenges of vaccine development.
Using novel vaccine technologies
Nucleic acid vaccines (RNA and DNA vaccines)
Nucleic acid vaccines, including RNA and DNA vaccines, are viewed as the next generation of vaccine technology. Nucleic acid vaccines are easy to design and manufacture, possess an excellent safety profile and are cost effective.
Of these, RNA vaccine platforms have gained immense popularity due to the recent approval of two mRNA vaccines for COVID-19, which took barely a year to be developed. In December 2020, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), became the first regulator in the world to grant authorization for the emergency use of Pfizer–BioNTech’s COVID-19 vaccine – the world’s first mRNA vaccine to gain approval. Clinical trials that evaluated mRNA vaccines in COVID-19 found them to be highly effective and safe.
mRNA vaccines can be manufactured synthetically without the use of toxic chemicals or cell cultures, hence safety concerns regarding the presence of cell-derived impurities and viral contaminants are reduced. Furthermore, the manufacturing of mRNA can be done rapidly, and the process is easily scalable. These properties make them suitable for the development of rapid response platforms.
mRNA vaccine technology is also being harnessed to develop vaccines for other debilitating conditions such as that caused by human immunodeficiency virus (HIV. It has been more than three decades since HIV was first discovered as the cause of acquired immunodeficiency syndrome (AIDS), but scientists have had little success developing vaccines to prevent HIV infection. This contrasts the rapid development process we have witnessed with the COVID-19 vaccine. "Unlike COVID-19, where the SARS-CoV-2 virus was relatively straightforward with respect to vaccine design, as the spike protein (S) and its receptor-binding domain (RBD) were quite accessible targets for inducing neutralizing antibodies to generate protective immunity, HIV presents many challenges," says Wayne Koff, president and CEO of the Human Vaccines Project and adjunct professor of epidemiology at the Harvard T.H. Chan School of Public Health.
Explaining the challenges, Koff continues, "First and foremost is the hypervariability of HIV-1, which dwarfs that of variable influenza, which in turn dwarfs that of SARS-CoV-2. Thus, to develop a safe and effective HIV-1 vaccine, one likely needs to induce broadly neutralizing antibodies and potentially broadly reactive cellular immune responses. Other challenges for HIV-1 include the limitations of animal models in predicting vaccine efficacy; the fact that HIV-1 infects cells of the immune system. Lastly, HIV is a retrovirus that integrates into the genome, making clearance of infection extremely difficult."
The advantages offered by the mRNA vaccines and the success observed in COVID-19 brings hope that the applicability of RNA vaccine platforms will be widened for HIV and other infectious diseases. "Progress continues to be made on the discovery of antigens for inclusion in HIV-1 vaccines, and vaccine strategies such as sequential immunization of different immunogens to generate broadly neutralizing antibodies – but unfortunately, the field remains years away from the successful development of an HIV-1 vaccine. Vaccine platforms such as mRNA can accelerate AIDS vaccine development – as they offer the potential for rapid screening of immunogens,” says Koff.
When asked if the mRNA vaccine platforms can be used to develop vaccines for cancer, Ben van der Zeijst, emeritus professor at the Leiden University Medical Center said, “Certainly yes. BioNTech started out with mRNA vaccines against cancer. There is presently much activity in this field.”
Advances in chemical and biological engineering have paved the way for the development of vaccines based on nanoparticles. In nanoparticle vaccines, protein antigens and carrier molecules are chemically cross-linked to enhance immunogenicity and stability. The physicochemical properties of the nanoparticles including the size, shape, solubility, functionality and surface chemistry, can be regulated to develop vaccines with the desired biological properties.
Nanoparticles shield antigens, the most essential component of a vaccine, from proteolytic degradation. They also enhance the antigen delivery to antigen-presenting cells. Antigens can be incorporated into the nanoparticles via encapsulation or by conjugation.
Stanford University researchers are developing a single-dose nanoparticle vaccine for COVID-19 that can be stored at room temperature. When tested in mice, the Stanford nanoparticle vaccine could produce SARS-CoV-2 immunity after just a single dose.
Using novel vaccine strategies
Structure-based vaccine design
With time, viruses evolve and generate host-evading mechanisms which may render them resistant to vaccines. A better knowledge of the viral structure, especially the antigen structure, can help decipher ways to understand and overcome the host-evading mechanisms and ultimately guide the design of novel vaccines against challenging viruses.
To better understand the structural details, advanced techniques such as X-ray crystallography, electron microscopy and computational biology are being used. These techniques can provide vital structural information about the viral envelope, protein conformation and antigenic epitopes which can help design antigens with better immunological features and biophysical characteristics.
"Quality by Design" framework to increase process robustness and scalability
The COVID-19 pandemic has highlighted the need for manufacturing technologies capable of producing large amounts of high-quality vaccines, quickly. Quality by Design (QbD) is a framework that can help in this regard.
The complexity and variability involved with the production of vaccine and biopharma products make it challenging to maintain product quality consistently in each batch. The current approach tests the product after it has been produced and if non-compliant to the quality standards, that batch is discarded. QbD is a systematic approach that integrates a novel qualitative methodology and a quantitative bioprocess model to support the development and consistent production of safe and efficacious vaccines. With QbD, safe, effective and high-quality vaccines as well as medicines can be produced consistently.
The implementation of the QbD framework follows an iterative development cycle. “The QbD framework supports both the development and operation of production processes and it follows an iterative development cycle to ensure continuous improvement through the product‐process life cycle,” says Zoltán Kis, research associate in the Future Vaccine Manufacturing Hub, Imperial College London.
The first step in the QbD framework is identifying the patients need, and then using a risk assessment type scoring, the critical quality attributes of the product is evaluated. Next, ways to control the production process are identified so that the product is produced consistently following all the critical quality attributes in the pre-defined ranges. “This allows for flexibility/adaptability in the production process, instead of running the cGMP production process at fixed settings (sometimes called “frozen” cGMP process),” says Kis.
The QbD model can be used to predict undesired changes in product quality ahead of time. This allows corrective measures to be taken early to fix the predicted faults. Another approach is the use of “digital twins”, in which QbD can be combined with models to better monitor and control the process. This is also called “Quality by Digital Design”. Kis explains further, “The models (once validated and approved by the regulatory authorities) can in principle predict ahead in time how the product quality will change. For example, if the models predict that the product quality will go out of specifications in the next 5-10 minutes, the corrective measures can be taken at the present moment to correct/fix those quality deviations before these occur (thus fixing faults in the quality before these occur). This could replace (at least partially) quality by testing with quality by design. This means that the quality can be built into (or assured by) the design and operation/automation of the production process.”
Artificial intelligence for vaccine development
Artificial intelligence (AI) can be an invaluable tool to design better vaccines. In fact, many of the COVID-19 vaccines owe their quick development to the power of AI.
“AI offers great potential for designing better vaccines- as the speed in which supercomputers, AI and machine learning, enables identification of novel sites of vulnerability on viral proteins such as HIV ENE and SARS-CoV-2 (S),” says Koff.
Machine-learning systems and computational analyses can help understand the virus and its structure and predict which of its components can contribute to an immune response. AI approaches can also be used to study the virus’s genetic mutations and understand how the virus evolves over time – this is especially relevant for conditions such as COVID-19, where several viral variants have emerged.
Though advantageous, AI alone is not sufficient. Koff explains, “AI alone will be less effective, at least in the short term, than coupling AI with structural modelling and wet-lab experimentation, to iteratively improve the AI models. In parallel, the generation of unprecedented scales of human immunity data, by the Human Vaccines Project and others, can help to facilitate the generation of initial AI models of human immunity – which will lead to future improvements of vaccine effectiveness in vulnerable populations, such as the elderly.”
Newer modes of vaccine delivery
Delivery is an important issue because most vaccines currently used are still administered intramuscularly, subcutaneously or intradermally with a hypodermic needle. Nasal vaccines, jet injectors, microneedles and nanopatches are some promising modes of vaccine delivery that may offer a painless, cost-effective, safe, and convenient option. These delivery strategies may also avoid the need for expensive cold‐chain transport and storage, an important issue in resource-constraint regions. Additionally, a painless delivery system can ensure better compliance with the vaccination schedule.
Intranasal vaccines offer a needle-free method of immunization that can be easier to use and distribute. “The need/benefit to using an aerosol vaccine will be directed by the indication of the type of immune response you need. If the infectious disease attacks the respiratory tract then it might be beneficial to have an aerosolized vaccine. If you need respiratory mucosal immunity an aerosolized vaccine could be beneficial,” explains Aurelio Bonavia from the vaccine development group at Bill & Melinda Gates Medical Research Institute. SARS-CoV-2 infections are found to trigger both systemic and mucosal immunity. Hence, administering vaccines through the nasal route is seen as a promising vaccine strategy. Another area where aerosol vaccines are being studied is tuberculosis.
Though an attractive mode of delivery, intranasal vaccines have gained little interest. But there are hopes that this perception may change once an internasal vaccine for COVID-19 is approved. Several challenges may hamper the development of intranasal vaccines. “Device, price, regulatory path, formulation, characterization of the aerosol particle and characterization of the immune response are some key challenges in developing an aerosolized vaccine,”, says Bonavia.
What does the future hold?
Applying a structure-based approach, using new vaccine platforms and leveraging automation are key to circumvent the challenges associated with the current vaccine development strategy. COVID-19 is a remarkable example of how advances in technology can enable the development of vaccines with increased efficiency within shorter time frames. Hopes are high that these novel approaches and development strategies can pave the way to develop vaccines against diseases in which the traditional approaches have failed.