Viral Emerging Diseases: Challenges in Developing Vaccination Strategies

Abstract

In the last decades, a number of infectious viruses have emerged from wildlife or re-emerged, generating serious threats to the global health and to the economy worldwide. Ebola and Marburg hemorrhagic fevers, Lassa fever, Dengue fever, Yellow fever, West Nile fever, Zika, and Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the recent Coronavirus disease 2019 (COVID-19) are examples of zoonoses that have spread throughout the globe with such a significant impact on public health that the scientific community has been called for a rapid intervention in preventing and treating emerging infections. Vaccination is probably the most effective tool in helping the immune system to activate protective responses against pathogens, reducing morbidity and mortality, as proven by historical records. Under health emergency conditions, new and alternative approaches in vaccine design and development are imperative for a rapid and massive vaccination coverage, to manage a disease outbreak and curtail the epidemic spread. This review gives an update on the current vaccination strategies for some of the emerging/re-emerging viruses, and discusses challenges and hurdles to overcome for developing efficacious vaccines against future pathogens.

Keywords: COVID-19; SARS-CoV-2; antibody-dependent enhancement; emerging infectious diseases; epidemics; pandemics; vaccines; viruses.

FIGURE 1

Timeline of emerging and re-emerging viral diseases. The year on the timeline is the year of the emergence or re-emergence of the schematically reported viral epidemic outbreaks within a certain geographic area; the overall given values of CFR (case fatality rate) refer to “the proportion of cases of a specified condition that are fatal within a specified time,” according to Dictionary of Epidemiology (228). SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; MERS-CoV, Middle East respiratory syndrome coronavirus; MARV, Marburg virus; YFV, Yellow Fever Virus; and LASV, Lassa virus.

FIGURE 2

Platforms for vaccine manufacturing: a graphical overview. Nucleic acid, viral-vector, protein-based, live attenuated and inactivated vaccines are schematically illustrated. Nucleic acid vaccines: conventional non-replicating mRNA vaccine, containing the target gene sequence, can be encapsulated into a delivery system to aid its cellular uptake. Once released from endosome into the cytosol, it is translated by the host cellular machinery into the target antigen. A pDNA carrying a gene target reaches the nucleus to achieve transcription and translation into the cytosol. pDNA can be internalized by somatic cells (i.e., myocytes) and then the secreted antigen can be taken up by APCs or naïve B cell, priming immune responses. Viral vectored vaccines: defective viral vector, carrying a transgene cassette, can be employed as a system to deliver a transgene and allow the expression of the heterologous antigen within the infected cell. A recombinant replicating viral vector retains the ability to replicate and produce progeny virus particles that can then infect cells, leading to transgene expression and Ag processing and presentation. Protein-based vaccines: recombinant subunit vaccine or a VLP can be taken up by APCs for MHC presentation and B-cell recognition through BCR. Virus vaccines: compared with an inactivated virus, a live attenuated virus retains the ability to replicate and infect cells, mimicking the natural infection. APCs, antigen-presenting cells; MHC, major histocompatibility complex; Ag, antigen; pDNA, plasmid DNA; EP, electroporation; BCR, B-cell receptor; and VLP, virus-like particle.

FIGURE 3

Antibody-dependent enhancement on Dengue infection. Antibodies generated from a previous DENV infection can recognize but do not neutralize another DENV serotype and can lead to antibody-dependent enhancement (ADE) of entry of the latter virus into host cells. The pre-existing non- (or sub-) neutralizing antibodies bind DENV through the Fab domains and mediate viral entry into FcγR-expressing cells. On engagement by the Fc domains, the virus–antibody immune complex is internalized by the activating FcγRIIa within the endosome. Co-ligation of FcγRIIa and LILRB1 (leukocyte immunoglobulin-like receptor-B1) to opsonized DENV drives the inhibitory signal cascade via immunoreceptor tyrosine-based inhibition motif (ITIM) pathway, abrogating the expression of ISGs (Interferon Stimulated Genes). Ligation of FcγRIIa to immune complex also increases Th2 cytokine production and reduces IFNγ, inhibiting the JAK/STAT signaling pathway, overall resulting in the suppression of the antiviral response and increase of viral replication. NAbs, neutralizing antibodies; and ITAM, immunoreceptor tyrosine-based activation motif.