Could live attenuated vaccines better control COVID-19?

Abstract

In an effort to control the COVID-19 pandemic, large-scale vaccination is being implemented in various countries using anti-SARS-CoV-2 vaccines based on mRNAs, adenovirus vectors, and inactivated viruses. However, there are concerns regarding adverse effects, such as the induction of fever attributed to mRNA vaccines and pre-existing immunity against adenovirus vectored vaccines or their possible involvement in the development of thrombosis. The induction of antibodies against the adenovirus vector itself constitutes another hindrance, rendering boosting vaccinations ineffective. Additionally, it has been questioned whether inactivated vaccines that predominantly induce humoral immunity are effective against newly arising variants, as some isolated strains were found to be resistant to the serum from COVID-19-recovered patients. Although the number of vaccinated people is steadily increasing on a global scale, it is still necessary to develop vaccines to address the difficulties and concerns mentioned above. Among the various vaccine modalities, live attenuated vaccines have been considered the most effective, since they closely replicate a natural infection without the burden of the disease. In our attempt to provide an additional option to the repertoire of COVID-19 vaccines, we succeeded in isolating temperature-sensitive strains with unique phenotypes that could serve as seeds for a live attenuated vaccine. In this review article, we summarize the characteristics of the currently approved SARS-CoV-2 vaccines and discuss their advantages and disadvantages. In particular, we focus on the novel temperature-sensitive variants of SARS-CoV-2 that we have recently isolated, and their potential application as live-attenuated vaccines. Based on a thorough evaluation of the different vaccine modalities, we argue that it is important to optimize usage not only based on efficacy, but also on the phases of the pandemic. Our findings can be used to inform vaccination practices and improve global recovery from the COVID-19 pandemic.

Keywords: COVID-19; Live attenuated vaccine; SARS-CoV-2; Vaccine.

Fig. 1

SARS-CoV-2 vaccine candidates under development. SARS-CoV-2 infects host cells through the binding of the spike protein with hACE2 that serves as receptor. Therefore, the spike protein is considered a target antigen for vaccine development. Recombinant spike protein, inactivated virus and virus-like particle vaccines are used as protein-based vaccines. Inactivated vaccines are treated with chemical reagents such as formalin and β-propiolactone. These treatments lead to the fixing of proteins or to genome damage (indicated by the dotted line), respectively. Virus-like particles are composed of structural proteins only, and do not contain the viral genome. They are structurally similar to the wild type particles, but the nucleocapsid proteins which bind to the viral genome, are not positioned correctly. Different approaches to deliver the spike-encoding gene into the cells include DNA plasmids, encapsulated RNAs or virus vectors. Moreover, live attenuated viruses can be developed by generating cold-adapted or temperature-sensitive strains, or by codon de-optimization.

Fig. 2

Live attenuated SARS-CoV-2 vaccine candidates. Cold-adapted mutants replicate more slowly in the lower respiratory tract and lungs, compared to the wild type strain. Temperature-sensitive mutants cannot replicate at these locations. Codon de-optimized mutants show lower proliferation rates than the wild type strain, at any location.

Fig. 3

Differential vaccine selection for specific pandemic stages. Vaccine characteristics that are optimal for specific pandemic stages are described. Rapidly developed vaccines, such as nucleic acid and recombinant virus vaccines, can impede the rise in cases of infection in the early stages of a pandemic. Humoral and cellular immunity targeting several antigens induced by live attenuated vaccines should be more effective during periods of high morbidity and mortality. After most of the population is immunized, highly safe vaccines, like recombinant protein-based vaccines, would be more appropriate to be administered as boosters.