Classical swine fever (CSF) is a highly contagious, economically significant, multi-systemic viral disease in swine [
1], which is notifiable to the World Organization for Animal Health (OIE). The causative agent, CSF virus (CSFV), is an enveloped, positive-sense, single-stranded RNA virus. It belongs to the
Pestivirus genus within the Flaviviridae family [
2]. Other members of this genus are bovine viral diarrhea virus (BVDV) 1 and 2, border disease virus (BDV), and an increasing number of tentative pestivirus species [
3,
4]. According to the recent reclassification of
Pestivirus genus by the International Committee on Taxonomy of Viruses (ICTV), BVDV-1 is re-designated as Pestivirus A, BVDV-2 is re-designated as Pestivirus B, CSFV is re-designated as Pestivirus C, BDV is re-designated as Pestivirus D, and many of tentative
Pestivirus species are re-designated as Pestivirus E-K [
5].The CSFV genome encodes a precursor polyprotein of 3898 amino acids (aa), which is post-translationally processed into four structural proteins (C, E
rns, E1 and E2) and eight non-structural proteins (N
pro, p7, non-structural protein [NS] 2, NS3, NS4A, NS4B, NS5A, and NS5B) by cellular and viral proteases [
6,
7]. Antibodies against the envelope glycoproteins E2, E
rns, and NS3 have been detected in pigs that recover from infection [
8,
9]. The major immunogen is the glycoprotein E2, in terms of inducing neutralizing antibodies and protection against future infection [
9,
10].
CSF has consistently caused important economic losses to the pig industry since its emergence [
11,
12]. Several countries have succeeded in eliminating CSF following the implementation of strict control measures. However, in most parts of the world with significant pig production, CSF is at least sporadically present. To date, CSF remains endemic in South and Central America, Eastern Europe, and neighboring countries, and Asia. Little is known about the African situation. The most recent outbreaks have been reported in Korea, Colombia, Russia, Brazil, and Japan [
13]. In particular, the reemergence of CSF from previously CSF-free Japan in September 2018 has caught much attention [
14,
15]. Thus, CSFV remains an endemic and reemerging virus in pigs and continues to threaten pork production worldwide and the food security of populations in developing countries.
Systematic vaccination and non-vaccination stamping-out are the two main strategies to control CSF [
16,
17]. In CSF-free zones, or where eradication is in progress, control is based on the non-vaccination and strict stamping-out policy. In contrast, due to the enormous costs of stamping-out, systematic prophylactic vaccination is a more effective strategy for CSF control in CSF endemic countries. As with many other viral infections affecting livestock, several highly efficacious live attenuated CSF vaccines have been widely used for decades and have paved the way to successful eradications in many areas. However, the use of these vaccines interferes with the serological diagnosis, as they lack differentiability of infected from vaccinated animals (DIVA). Indeed, due to the trade restrictions that are imposed on pigs vaccinated with conventional live attenuated vaccines, only DIVA vaccines are considered a feasible option for future control and eradication of CSF. Therefore, the development of potent DIVA vaccines poses a challenge for research groups worldwide. So far, different concepts have been investigated during the development of CSFV DIVA vaccines, including vector vaccines, recombinant attenuated vaccines with chimeric constructs, subunit vaccines, peptide vaccines, and RNA/DNA vaccines. This review is aimed at describing progress and challenges associated with CSFV vaccine development, revealing the strategies and approaches that may also be helpful for the development of next-generation vaccines against other pathogens.