Sung J. Yoo

The emergence of immune-evasive SARS-CoV-2 Omicron subvariants highlights the need to develop a mucosal SARS-CoV-2 vaccine that can provide broad protection against virus infection and transmission. Here, we developed an intranasal monovalent SARS-CoV-2 vaccine expressing the six-proline-stabilized prefusion spike proteins (preS-6P) of Omicron XBB.1.5 based on the attenuated mumps virus (MuV) Jeryl Lynn (JL1) vaccine strain. We also developed an intranasal trivalent vaccine expressing the preS-6P of ancestral SARS-CoV-2 WA1 and two Omicron subvariants, BA.1 and XBB.1.5, using the attenuated measles virus (MeV) and MuV-JL1 and JL2 vaccine strains, respectively. Intranasal immunization of hamsters with the monovalent rMuV-JL1-XBB.1.5 or the trivalent vaccine induced high levels of neutralizing antibodies (NAbs) that efficiently neutralized Omicron subvariants XBB.1.5, EG.5, and JN.1, providing complete protection against these Omicron subvariants. Similar levels of Omicron XBB.1.5 NAbs were detected in monovalent rMuV-JL1-XBB.1.5 and trivalent vaccine groups even when hamsters had been preimmunized with the rMuV-JL2-WA1 vaccine, suggesting that both intranasal vaccines are effective in the presence of immune imprinting induced by the spike of SARS-CoV-2 WA1. Intranasal, but not subcutaneous, immunization generated high levels of S-specific mucosal IgA antibodies as well as lung-resident memory T cells in IFNAR1^-/- mice. Finally, intranasal immunization with the trivalent vaccine efficiently blocked transmission of SARS-CoV-2 WA1 and Omicron XBB.1.5 among hamsters in a direct contact transmission setting. In summary, we have developed intranasal MeV and MuV-based trivalent vaccines that induce broad NAbs, robust mucosal immunity, and strong protection against both virus challenge and virus transmission.

As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1^−/− mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate.

As SARS-CoV-2 variants of concern (VoCs) that evade immunity continue to emerge, next-generation adaptable COVID-19 vaccines which protect the respiratory tract and provide broader, more effective, and durable protection are urgently needed. Here, we have developed one such approach, a highly efficacious, intranasally delivered, trivalent measles-mumps-SARS-CoV-2 spike (S) protein (MMS) vaccine candidate that induces robust systemic and mucosal immunity with broad protection. This vaccine candidate is based on three components of the MMR vaccine, a measles virus Edmonston and the two mumps virus strains [Jeryl Lynn 1 (JL1) and JL2] that are known to provide safe, effective, and long-lasting protective immunity. The six proline-stabilized prefusion S protein (preS-6P) genes for ancestral SARS-CoV-2 WA1 and two important SARS-CoV-2 VoCs (Delta and Omicron BA.1) were each inserted into one of these three viruses which were then combined into a trivalent “MMS” candidate vaccine. Intranasal immunization of MMS in IFNAR1 ^−/− mice induced a strong SARS-CoV-2-specific serum IgG response, cross-variant neutralizing antibodies, mucosal IgA, and systemic and tissue-resident T cells. Immunization of golden Syrian hamsters with MMS vaccine induced similarly high levels of antibodies that efficiently neutralized SARS-CoV-2 VoCs and provided broad and complete protection against challenge with any of these VoCs. This MMS vaccine is an efficacious, broadly protective next-generation COVID-19 vaccine candidate, which is readily adaptable to new variants, built on a platform with a 50-y safety record that also protects against measles and mumps.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen that affects the global swine industry. The continuous evolution of this virus has made control and prevention difficult, which emphasizes the importance of monitoring currently circulating PRRSV strains. In this study, we investigated the genetic characteristics of whole structural genes of 35 PRRSV-2 isolates that circulated between 2012 and 2017 in Korea. Genetic and phylogenetic analysis demonstrated that a recently identified PRRSV-2 shared a relatively low level of nucleotide sequence identity that ranged from 86.2% to 92.8%; however, they were clustered into four distinct Korean field clades, except KU-N1702, in ORF2–7-based phylogeny. KU-N1702 was closely related to the NADC30-like strains that were identified in the USA and China. Amino acid sequence analysis showed that the GP5 neutralizing epitope was conserved among the KU viruses. In contrast, the viruses had genetic mutations in key residues for viral neutralization within GP5 and M. For minor structural proteins, neutralizing epitopes, aa 41–55 of GP2, 61–75 of GP3, and 51–65 of GP4, were variable among the KU viruses. Bioinformatics demonstrated diversifying evolution within the GP2 and GP4 neutralizing epitopes and the emergence of a novel glycosylation site within the GP3 and GP4 neutralizing epitopes. Taken together, these data provide evidence that Korean PRRSV-2 evolved independently in Korea, with genetic heterogeneity in antigenic regions of structural proteins.

We report classical swine fever outbreaks occurring in naive pig herds on Jeju Island, South Korea, after the introduction of the LOM vaccine strain. Two isolates from sick pigs had >99% identity with the vaccine stain. LOM strain does not appear safe; its use in the vaccine should be reconsidered.

Nationwide porcine epidemic diarrhea virus (PEDV) outbreaks occurred in late 2013 in the Republic of Korea, resulting in an expansion of genomic data for Korean PEDVs. However, the data available for Korean PEDVs before 2013 are insufficient. Therefore, we sequenced and analyzed the complete genome of a Korean PEDV strain, KUPE21, which was isolated in the early 2000s.

Modified live vaccines (MLVs) based on genotype 1 strains, particularly C-strain, have been used to prevent and control classical swine fever virus (CSFV) worldwide. Nevertheless, a shift in the predominant CSFV strains circulating in the field from genotype 1 or 3 to genotype 2 is seen. Genotype 2 is genetically distant from the vaccine strains and was recently reported during outbreaks after vaccine failure; this has raised concerns that vaccination has influenced viral evolution. In Korea in 2016, there was an unexpected CSF outbreak in a MLV-vaccinated commercial pig herd. The causative CSFV strain was genetically distinct from previously isolated Korean strains but similar to recent Chinese strains exhibiting enhanced capacity to escape neutralization; this suggests the need for global cooperative research on the evolution of CSFV. We analysed global E2 sequences, using bioinformatics tools, revealing the evolutionary pathways of CSFV. Classical swine fever virus genotypes 1 and 2 experienced different degrees and patterns of evolutionary growth. Whereas genotype 1 stayed relatively conserved over time, the genetic diversity of genotype 2 has progressively expanded, with few fluctuations. It was determined that genotype 2 evolved under lower immune pressures and at a higher evolutionary rate than genotype 1. Further, several selected codons, under diversifying selection in genotype 1 but under purifying selection in genotype 2, correspond to antigenic determinants, which could lead to evasion of vaccine-induced immunity. Our findings provide evidence that evolutionary changes in CSFV are the result of the disproportionate usage of the CSF MLVs in endemic areas; this underscores the need to develop mitigation strategies to minimize the substantial risk associated with the emergence of vaccine-escaping mutants.

Je SH, et al. Clin Exp Vaccine Res. 2018 Jul;7(2):139-144. https://doi.org/10.7774/cevr.2018.7.2.139

Yoo SJ, et al. Clin Exp Vaccine Res. 2018 Jan;7(1):1-15. https://doi.org/10.7774/cevr.2018.7.1.1