1. Type of vaccine
Advances in virology, molecular biology, and immunology have created many alternatives to traditional vaccines. Modern vaccines include nucleic acid (mRNA, DNA) vaccines, viral vector vaccines, virus-like particles and recombinant protein vaccines. All types of vaccines are brought to the forefront of the fight against the COVID-19 pandemic. Due to the high speed of cloning and synthesis, mRNA and DNA vaccines first entered the vaccine track in the United States. Some vaccines contain PAMPs of endogenous (vaccine virus genome) or vaccine inherent components (inactivated virus genome). Others without PAMPs need adjuvants. Except for some live attenuated vaccines that produce antigens for a long time, most vaccines need to be injected to improve the antibody response and affinity.
2. Progress and challenges of vaccine
Vaccine has yet to conquer the world’s deadliest and debilitating infections: malaria, Mycobacterium tuberculosis, and HIV-1. These pathogens are difficult to deal with because we still do not know how to cause protective immunity or how to combat the escape mechanism of pathogens. However, there is promising progress in the fight against these pathogens. Malaria is caused by malaria parasites with complex life cycles and numerous antigens. RTS, S/AS01 malaria vaccine is the most advanced vaccine candidate, and phase 3 clinical trials have been completed. The vaccine prevented 39% of malaria cases and 29% of severe malaria cases during 4-year follow-up, making it the first vaccine to significantly reduce infection and disease. The vaccine consists of circumsporozoite protein of Plasmodium falciparum and envelope protein of hepatitis B virus with AS01 as adjuvant. Based on this encouraging result, pilot vaccination was launched in three countries, Malawi, Ghana, and Kenya in 2019. Pilot vaccination is expected to last till 2023.
M72/AS01E, another candidate for tuberculosis therapeutics, is reported to have made a breakthrough. In a phase 2 clinical trial in Kenya, South Africa, and Zambia, the vaccine had a significant preventive effect on latent TB infections. M72 is a fusion protein vaccine consisting of two subunits of MTB antigens (32A and 39A) with AS01E as adjuvant. After 2 years of follow-up, the protection rate of active tuberculosis of the vaccine was 54.0%.
In terms of HIV-1 vaccine, although a lot of energy and resources have been invested, many candidate vaccines failed to show effectiveness in clinical trials. In addition to HIV-1, there are many neglected tropical diseases that also need effective vaccines.
3. The Development of Vaccine Science
Systems vaccinology combined with systems biology methods of multidisciplinary high-dimensional data sets, from the discovery stage of vaccine design to clinical trial response prediction and improved implementation strategies, all provide better information for vaccines. Systemic vaccinology is applied widely, including influenza virus and yellow fever, and has revealed an unexpected correlation between genetic markers and vaccine efficacy. In addition, systematic serological methods have been applied to HIV-1 vaccines. Another emerging field of vaccinology is T-cell vaccines. Although antibodies are the focus of almost all vaccines, not all viruses can adapt to antibody-dependent immunity. Some viruses have the ability to avoid antibodies, including HIV-1 (evading antibody recognition through rapid mutation), influenza virus (through antigen drift to avoid antibody recognition), and herpes simplex virus (invalidating antibodies through the expression of evasin molecules on the surface of virions). For these viruses that escape antibodies, we need different vaccination methods. Fortunately, there are some conserved epitopes that can be vaccinated to produce T-cell immunity. A key aspect of T-cell immunity is that T cells work best if they already exist at the entrance, such as the mucosal surface. However, vaccines injected into muscles often fail to induce memory T cells in mucus. The two-step vaccine strategy, namely primary immunization-attraction (prime and pull) strategy, can solve this distribution problem by using chemokine or chemokine inducer to recruit and establish tissue resident memory T cells in selected tissues (the main pathway for virus entry). T-cell-based vaccines are expected to be used for antibodies to evade pathogens and cancer vaccines with no surface antigens to target. Another frontier of vaccine science is the development of mucosal vaccines. With the exception of vector carriers, most pathogens enter the body through the mucosal surface. Unlike the skin, the mucosal epithelium is vulnerable to pathogens due to a lack of keratosis. There are two types of mucosal surface: type 1 is composed of a single layer of columnar epithelium (such as intestine, lung, and cervix), while type 2 is composed of layered squamous epithelium (such as eyes, nose, vagina, and cervix).
These two types of epithelium are protected by different adaptive immune mechanisms, so the vaccine should cause the corresponding types of responses. It is worth noting that type 1 mucosal epithelial cells express polymeric immunoglobulin receptor (pIgR), which can transport dimer IgA to the lumen, thereby neutralizing incoming pathogens or toxins. Type 2 mucosal surface is deficient in pIgR, and protected by IgG. Both types of mucosa can carry tissue resident memory T cells. Mucosal immunity provides an opportunity to completely block infection or aseptic immunity. Because dendritic cells can guide T cells to migrate to mucosal tissue, vaccine delivery through mucosal surface (intranasal and oral) is more effective than parenteral transmission vaccine in establishing local immune memory and response. In addition, based on the mechanism of mucosal dendritic cells promoting mucosal homing T cells, a parenteral vaccine can be designed to induce mucosal immunity. However, the vast majority of approved vaccines are injected into muscles without any promotion of mucosal immune design. If a safe and effective vaccine can establish strong mucosal immunity at the site of pathogen invasion, it will change the application prospect of the vaccine.
4. How to improve the acceptance of vaccine
Finally, a major obstacle to establishing and maintaining mass immunity with vaccines is the low acceptance of vaccines in some groups due to misinformation and mistrust. Vaccines greatly relieve the burden of many diseases, making a large number of parents unfamiliar with once-common diseases such as measles. People often hear or perceive adverse events of the vaccine through the information spread by social media. Declining awareness of the severity of vaccine-preventable diseases and concerns about the safety of vaccines make people hesitant to receive vaccines. Low trust in government and healthcare providers is also associated with low acceptance of vaccines.
Fortunately, some progress has been made in developing and deploying interventions to improve vaccine acceptance. It is reported that presumptive communication is an effective method to improve the acceptance of vaccine. In addition, it has been proved that structural interventions that makes vaccination easy and convenient can increase the prevalence of immunization.
At present, vaccines remain one of the most effective tools for preventing morbidity and mortality caused by endemic diseases and emergency threats. Recent advances in vaccine science may herald another golden era of vaccines. In the future, vaccine science must learn from not only virology, immunology, bioinformatics, and systems biology, but also social sciences.