The future of vaccination in a post-COVID-19 world

In 2019, the WHO estimated that vaccines were responsible for saving 4 to 5 million lives a year globally¹. In 2020, we witnessed a coronavirus disrupt the planet in a way no pathogen has before². The full-scale assault that followed led to the most rapid development of a vaccine to date^3,4. The COVID-19 pandemic has instilled optimism in many that the development of novel and improved vaccines against other pathogens responsible for major public health issues is more achievable now than ever^4,5.

With continued research efforts, soon it may be possible to:

• Develop novel vaccines against pathogens for which there is currently no available vaccine (e.g., chronic infections like human immunodeficiency virus [HIV] and hepatitis C)^6,7

For more on HIV and hepatitis C vaccine efforts, see: ‘Why do we not have vaccines for HIV and hepatitis C? An overview of current challenges’

• Improve the efficacy and/or uptake of existing vaccines for diseases that are not well-managed (e.g., human papillomavirus [HPV])⁸
• Enhance the efficacy and/or uptake of existing vaccines for well-managed diseases and potentially eradicate these infections completely (e.g., acute infections like measles, mumps, rubella, varicella, herpes zoster)^9–11

For more on herpes zoster vaccines, see: ‘From chickenpox to shingles: The developmental history of herpes zoster vaccines’

Here we review recent advances, key areas for improvement, and future directions in the technology and clinical application of vaccines.

mRNA vaccines

The first vaccine to be approved against COVID-19 was also the first prophylactic mRNA vaccine to be developed⁵. The unprecedented success has largely been attributed to the recent advances in mRNA delivery systems¹².

mRNA vaccines have been demonstrated to be highly effective, meet the necessary safety criteria, and have numerous advantages as a vaccine strategy¹³. As the mechanism of action is contained in the cytosol of the cells, mRNA vaccines do not have the concerns of genomic disruption and off-target effects as with DNA vaccines⁴. Modification at the nucleic acid level is easy and can improve the half-life and safety of the vaccine⁴. Production of mRNA vaccines is rapid, straightforward, and easily scalable⁴. Hence, the potential for developing mRNA vaccines against other diseases is strong and investigations are underway to develop vaccines against many acute and chronic infections including influenza, HIV, zika virus and dengue fever⁴.

We are likely to see more mRNA vaccines in the future, however, the technology is not without flaws and can be improved^4,5. Increasing the targeting of dendritic cells via surface conjugation of specific ligands could improve vaccine efficacy⁴. Alternative mRNA delivery materials could improve vaccine safety¹². In addition, current mRNA vaccines require storage in low temperatures making transport and administration of doses challenging, particularly for developing countries with warmer climates⁴.

Some investigations have shown success in animal models using an mRNA vaccine without any delivery system^4,12. These ‘self-amplifying’ mRNA vaccines contain mRNA encoding an alphavirus RNA-dependent RNA polymerase, plus a second mRNA that encodes the antigen of interest¹². The alphavirus component enables its own replication in the cytoplasm¹². Self-amplifying (or self-replicating) mRNA vaccines may represent the next new generation of mRNA vaccines as they allow a sustained immune response, have a simplified production method, and it could mean the vaccine does not have to be stored in low temperatures^4,12.

Use of CRISPR/Cas9

Currently, the use of the CRISPR/Cas9-based gene editing technology with viruses sits within the basic research space¹⁴. In comparison with other gene editing techniques, CRISPR/Cas9 is more efficient, specific, versatile, flexible, simple, and cost-effective¹⁴. As such, there is little doubt that this technology provides endless possibilities¹⁴. One of those possibilities is to modify the genome of a pathogen by gene deletion, substitution, and/or insertion to create vaccine candidates¹⁴. The editing of functional genes can also facilitate our understanding of viral pathogenesis and viral-host interactions¹⁴.

Several anti-viral vaccines for animals have been developed using the CRISPR/Cas9 system¹⁴. However, a long-term observation period is required to assess the editing efficiency and stability required, so whilst its feasible, it may be some time before we see a potential clinical application in humans¹⁴.

Vaccine awareness and acceptance

For vaccines to have an impact in the real world, it is essential for the public to be aware of what vaccines are available, and the associated benefits and risks¹⁵. As multiple studies have shown, poor education and lack of knowledge are frequently to blame for individuals not vaccinating¹⁶. In addition, we also frequently see the spread of misinformation about vaccines¹⁵.

Unfortunately, the relationship between knowledge and vaccine acceptance is not one of direct correlation so simply providing more information to the public will not automatically improve acceptance¹⁶. This is a key area for improvement in the vaccine field. What we may see more of in the future is the utilisation of risk communication strategies¹⁵. Healthcare professionals are in an excellent position to utilise these strategies, discuss the benefits and risks of vaccines with patients, and address any misconceptions¹⁵. Managing risk communication is particularly important because adverse events associated with vaccination represent a major cause of vaccine hesitancy¹⁵.

Vaccine hesitancy is a growing concern and was identified by the WHO as one of the top ten threats to global public health even before the COVID-19 pandemic¹⁷. Individuals who are vaccine-hesitant may delay or be reluctant to accept some or all vaccines¹⁵. Such hesitancy often reflects legitimate doubts about vaccine safety and/or more general concerns about the pharmaceutical industry, governments, and healthcare professionals¹⁵. In the future, we may see stronger policies for mandatory immunisation policies¹⁵. Whilst mandatory vaccines have been shown to be effective in increasing vaccine uptake, vaccine hesitancy is not directly addressed and resides¹⁵.

Vaccine adherence

The typical intramuscular route of administration for almost all vaccines causes localised pain and often multiple doses are required for full protection which can affect patient adherence to an immunisation schedule¹⁸. In addition, individuals who are needle-phobic may be vaccine-hesitant¹⁹.

The nasal influenza vaccine and oral polio vaccine are among the few non-intramuscular vaccines that exist and have been incredibly successful in increasing vaccine adherence¹⁸. Many clinical trials with vaccines using pulmonary or nasal delivery systems are underway, with these trials targeting acute and chronic infections including meningitis, influenza, respiratory syncytial virus, and tuberculosis¹⁸. Oral vaccines are probably the most patient-friendly and research is underway to bypass the challenges of developing oral vaccines against other infectious diseases^18,20. Topical or intradermal routes, including the use of microneedles, are also under investigation¹⁸. Hence, in the future, it is likely that more vaccines that use a non-intramuscular route of administration will be availiable¹⁸.

Targets for 2030

The World Health Organization’s Immunisation Agenda 2030 sets the strategy to achieve the vision of ‘a world where everyone, everywhere, at every age fully benefits from vaccines for good health and well-being’²¹. Disease-specific targets have also been set, for example, to eliminate hepatitis C globally by 2030²². Learnings from COVID-19 research can help us to achieve these targets and have turbocharged the development of vaccines against other infectious diseases^4,5. Whilst the future of vaccination is promising, it depends on the success of continued medical research and increased vaccine acceptance.

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