Since the discovery of messenger RNA (mRNA), there have been tremendous efforts to wield them in the development of therapeutics and vaccines. During the COVID-19 pandemic, two mRNA vaccines were developed and approved in record-breaking time, revolutionizing the vaccine development landscape. Although first-generation COVID-19 mRNA vaccines have demonstrated over 90% efficacy, alongside strong immunogenicity in humoral and cell-mediated immune responses, their durability has lagged compared to long-lived vaccines, such as the yellow fever vaccine. Although worldwide vaccination campaigns have saved lives estimated in the tens of millions, side effects, ranging from mild reactogenicity to rare severe diseases, have been reported. This review provides an overview and mechanistic insights into immune responses and adverse effects documented primarily for COVID-19 mRNA vaccines. Furthermore, we discuss the perspectives of this promising vaccine platform and the challenges in balancing immunogenicity and adverse effects.

​Summary: Globally, infection by seasonal influenza viruses causes 3–5 million cases of severe illness and 290,000–650,000 respiratory deaths each year. Various influenza vaccines, including inactivated split‐ and subunit‐type, recombinant and live attenuated vaccines, have been developed since the 1930s when it was discovered that influenza viruses could be cultivated in embryonated eggs. However, the protection rate offered by these vaccines is rather low, especially in very young children and the elderly. In this review, we describe the history of influenza vaccine development, the immune responses induced by the vaccines and the adjuvants applied. Further, we suggest future directions for improving the effectiveness of influenza vaccines in all age groups. This includes the development of an influenza vaccine that induces a balanced T helper cell type 1 and type 2 immune responses based on the understanding of the immune system, and the development of a broad‐spectrum influenza vaccine that can increase effectiveness despite antigen shifts and drifts, which are characteristics of the influenza virus. A brighter future can be envisaged if the development of an adjuvant that is safe and effective is realized.

The relationship between obesity and vaccine efficacy is a serious issue. Previous studies have shown that vaccine efficacy is lower in the obese than in the non-obese. Here, we examined the influence of obesity on the efficacy of influenza vaccination using high fat diet (HFD) and regular fat diet (RFD) mice that were immunized with 2 types of influenza virus vaccines-cell culture-based vaccines and egg-based vaccines. HFD mice showed lower levels of neutralizing antibody titers as compared with RFD mice. Moreover, HFD mice showed high levels of MCP-1 in serum and adipocytes, and low level of influenza virus-specific effector memory CD8(+) T cells. After challenge with influenza virus, the lungs of HFD mice showed more severe inflammatory responses as compared with the lungs of RFD mice, even after vaccination. Taken together, our data suggested that the inflammatory condition in obesity may contribute to the suppressed efficacy of influenza vaccination.

In response to the COVID-19 pandemic, different types of vaccines, such as inactive, live-attenuated, messenger RNA (mRNA), and protein subunit, have been developed against SARS-CoV-2. This has unintentionally created a unique scenario where heterologous prime-boost vaccination against a single virus has been administered to a large human population. Here, we aimed to analyze whether the immunization order of vaccine types influences the efficacy of heterologous prime-boost vaccination, especially mRNA and protein-based vaccines. We developed a new mRNA vaccine encoding the hemagglutinin (HA) glycoprotein of the influenza virus using the 3′-UTR and 5′-UTR of muscle cells (mRNA-HA) and tested its efficacy by heterologous immunization with an HA protein vaccine (protein-HA). The results demonstrated higher IgG2a levels and hemagglutination inhibition titers in the mRNA-HA priming/protein-HA boosting (R-P) regimen than those induced by reverse immunization (protein-HA priming/mRNA-HA boosting, P-R). After the viral challenge, the R-P group showed lower virus loads and less inflammation in the lungs than the P-R group did. Transcriptome analysis revealed that the heterologous prime-boost groups had differentially activated immune response pathways, according to the order of immunization. In summary, our results demonstrate that the sequence of vaccination is critical to direct desired immune responses. This study demonstrates the potential of a heterologous vaccination strategy using mRNA and protein vaccine platforms against viral infection.