HIV vaccines

In the case of HIV, much has been achieved during the past ten years in the area of antiviral drugs to provide therapeutic efficacy resulting in non-detectable levels of the virus load in AIDS patients [17]. However, the treatment requires a cocktail of several drugs, whereas vaccines might be more straightforward and can be applied for both prophylactic and therapeutic activities.

The design of first-generation HIV-1 vaccines focused on neutralizing antibodies, whereas more recent development has involved T-cell responses and non-neutralizing antibodies against HIV structural proteins [18–20]. In a review, 21 clinical trials based on seven viral vectors, three DNA plasmids, four envelope proteins, five adjuvants, and three monoclonal antibodies (mAbs) conducted in South Africa were described [21]. In another review, HIV vaccines based on protein subunits, viral vectors, nucleic acids, and germline targeting have been described [22]. For example, a modified vaccinia Ankara (MVA) vector expressing the HIV gag p24 and p17 antigens showed no serious adverse events but some severe local reactions in a phase I trial [23] (Table 1). Due to the low and short immune responses achieved, the trial was terminated early. In another phase I trial conducted in HIV-uninfected adults, the Venezuelan equine encephalitis virus (VEE) vector expressing the HIV-1 subtype C gag (AVX101) was terminated due to vaccine stability issues and limited immune responses in humans [24]. Moreover, the canarypox vector-based vaccine canarypox virus (ALVAC)-HIV (vCP1521) was generally safe and well-tolerated in phase I [25]. In comparison to the RV144 phase III trial in Thailand with the ALVAC/AIDSVAX vaccine [26], the higher peak cellular and antibody responses were obtained for ALVAC-HIV (vCP1521). However, the Env-specific IgG and CD4+ Env responses declined significantly over time. In another approach, an adeno-associated virus (AAV) vector was engineered to express broadly neutralizing antibodies (bnAbs) [27], designed to bind two different antigens or epitopes simultaneously. Application of bnAbs should provide superior potency, broader coverage, and reduce risk of viral escape. Based on this approach, a tri-specific antibody binding to CD4 binding sites, membrane proximal external regions, and V1V2 glycan sites showed an extraordinarily broad activity in vitro [28]. However, these findings need to be confirmed in clinical trials. A phase I study has been conducted with AAV delivery of bnAbPG9 for prevention of HIV in healthy adults [29]. Although the study was safe, the elicited antibody levels were low.

Vaccines based on lipid nanoparticle (LNP) encapsulated mRNA have also been developed for HIV. The HVTN302 phase I trial was conducted with three different stabilized HIV envelope trimer antigens [30]. The vaccination was generally well tolerated, although a higher proportion (6.5%) of urticaria compared to other mRNA vaccines was detected. Neutralizing antibodies were elicited in 80% of vaccinees after three immunizations.

An interesting promising new approach relates to germline targeting [31]. It can be achieved by the design of a series of immunogens for the stimulation of rare naïve B cells for the induction of broadly neutralizing activity. The germline-targeting immunogen eOD-GT8 60mer, an outer domain of HIV gp120, was presented on nanoparticles in the G001 phase I trial [32]. Detectable B-cell expression of VRC01-class precursors was found in 97% of individuals receiving eOD-GT8 and the immunogen effectively primed the immune system [32]. Another phase I trial (G002) is in progress to study the safety and immunogenicity after booster vaccinations with the gp120 core-based nanoparticle immunogen (Core-g28v2 60mer) [33].

HPV vaccines

Effective prophylactic vaccines against HPV have been developed based on virus-like particles (VLPs), self-assembled spontaneously from the HPV L1 major capsid protein to target cervical cancer [34]. VLPs are non-infectious supramolecular structures, which resemble original viruses in shape and structure, but do not contain a functional genome. The Cervarix vaccine (GlaxoSmithKline), based on L1 VLPs from HPV-16 and HPV-18, is produced in baculovirus-infected insect cells [35], whereas the Gardasil vaccine (Merck & Co) VLPs from HPV-16, HPV-18, HPV-6 and HPV-11 are produced in Saccharomyces cerevisiae yeast cells [36]. Furthermore, Gardasil 9 was developed to contain VLPs from five additional oncogenic types of HPV (HPV-31, 33, 45, 52 and 58), which provided type-specific protection against 90% of cervical cancers worldwide [37]. In a systematic review and network meta-analysis based on 11 randomized clinical studies, vaccine efficacy was determined for bivalent (2vHPV), quadrivalent (4vHPV), and nine-valent HPV (9vHPV) vaccines [38]. The 2vHPV vaccine was most effective at 98% (95% CI 0.00 to 0.29) against HPV-18, whereas 4vHPV was superior at 99% (95% CI 0.00 to 0.10) and 97% (95% CI 0.00 to 0.45), respectively, for cervical intraepithelial neoplasia grade 2+ (CIN2+) associated with HPV-16 and HPV-18. In the case of persistent infection with HPV-31, 33, 45, 52, and 58, 9vHPV showed more than 95% vaccine effectiveness. Additionally, the 2vHPV vaccine demonstrated cross-effectiveness against HPV-31, 33, and 45, and the 4vHPV vaccine against HPV-31.

The successful development of these prophylactic HPV vaccines has, however, not addressed the need for the treatment of existing HPV lesions in cancer patients. For this reason, self-amplifying RNA (saRNA) viruses have been utilized for immunotherapeutic applications. Typically, saRNA viruses carry replicase genes responsible for efficient RNA replication in host cells, requiring reduced doses, leading to enhanced durability and potentially causing fewer adverse events. They can be applied as recombinant viral particles, RNA replicons, or DNA plasmids. Replication-deficient Semliki Forest virus (SFV) particles have been engineered for the expression of the HPV E6/E7 fusion proteins, resulting in regression and complete elimination of established tumors in tumor-bearing mice [39]. The SFV-HPV E6/E7 vaccine was safe and well tolerated in patients with HPV-induced cancers in phase I [40]. Moreover, strong immune responses against HPV-16 were detected in all 12 patients. Furthermore, in phase II, 18 patients with CIN3 were vaccinated with SFV-HPV E6/E7, resulting in a reduction in lesions in 94% of the patients three weeks post-vaccination [41]. Based on histopathologic evaluation, complete responses were obtained in 50% of the patients, and HPV-16 clearance was seen in 63% of patients.

EBOV vaccines

EBOV disease (EVD) is characterized by its rapid onset and high mortality rates after EBOV infections, which has encouraged vaccine development [42]. The administration of VEE particles expressing the EBOV glycoprotein (GP) and nucleoprotein (NP) protected both mice and guinea pigs against challenges with lethal doses of EBOV [43]. Moreover, expression of the EBOV GP from the Zaire strain from vesicular stomatitis virus (VSV) particles [rVSV-ZEBOV (Zaire EBOV)] showed excellent efficacy in phase III trials in Guinea and Sierra Leone [44, 45]. Although by definition, vaccine efficacy should be addressed in clinical trials, the authors mention that the rVSV-ZEBOV vaccine showed 75.1% (95% CI 7.1 to 94.2%; p = 0.1791) vaccine effectiveness for eligible adults and 76.3% (95% CI 15.5 to 95.1%; p = 0.3351) for individuals eligible and not eligible for vaccination [44]. In the other phase III trial [45], the vaccination effectiveness of protection was 100% (95% CI 68.9 to 100.0%; p = 0.0045). The rVSV-ZEBOV vaccine was approved by the Food and Drug Administration (FDA) in 2019 [46].

In another approach, the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen was assessed for safety and immune memory responses after booster vaccination with Ad26.ZEBOV in healthcare and front-line workers in the Democratic Republic of Congo in a phase II trial [47]. The vaccinations were well tolerated, and similar robust humoral immune responses were detected in individuals receiving the booster vaccination one or two years after the first dose, indicating the advantage of booster vaccinations in at-risk individuals. The Ad26.ZEBOV-GP vaccine (Zabdeno) was approved by the European Medicines Agency (EMA) in 2020 [48].

Influenza virus vaccines

The development of vaccines against influenza viruses has become familiar to everybody due to the annual flu epidemics and the engineering of novel vaccines each year to challenge emerging new influenza virus variants [49, 50].

Numerous approaches have been applied for influenza vaccine development, including vaccines based on whole viruses, protein subunits, virosomes, viral vectors and mRNA [51]. For example, live attenuated influenza viruses have been engineered by the introduction of mutations or by passaging parental influenza virus multiple times in virus-susceptible cells of embryonic chicken eggs. Low virulence strains containing for example, influenza A (H1N1) and A (H3N2) subtypes, are tested in human volunteers before being approved by the FDA as vaccines [52]. For example, both live attenuated influenza virus vaccines and inactivated influenza virus vaccines showed effectiveness of 50% (95% CI 2 to 75%) and 71% (95% CI 51 to 82%), respectively, in children of 2 to 17 years when compared to unvaccinated children [53]. The approach of developing inactivated whole influenza virus vaccines can provide high safety, robust and long duration of immunogenicity, and no risk of reversion of virulence [54, 55]. Several inactivated whole influenza virus vaccines have been approved [56]. In another approach, split-virion vaccines have been engineered by disrupting the viral envelope and splitting open the viral particles, providing additional safety compared to inactivated whole virus vaccines [57]. Good safety and strong immunogenicity were achieved in a phase IV trial in China with the split-virion influenza virus vaccine Aleph [58]. The trivalent IIV3 and quadrivalent IIV4 inactivated influenza vaccines have been approved for marketing in China [59].

Vaccines have also been developed based on virosomes, which comprise reconstituted influenza virus envelopes containing hemagglutinin (HA), neuraminidase (NA) and viral phospholipids [60, 61]. Two virosome-based vaccines reached the market in the 1990s: Epaxal^® against hepatitis A [62] and Inflexal^® V against influenza virus [63]. Moreover, the adjuvanted influenza virosome-based Inflexal V vaccine demonstrated good immunogenicity in healthy adults aged 18–60 years [64].

Different viral vectors have been utilized for influenza virus vaccine development. For example, adenoviruses expressing the conserved antigenic regions of the stem region of HA2, chimeric HA, M2e, NP, and T/B cell epitopes elicited robust immunogenicity and protection against different subtypes of influenza viruses [65, 66]. Furthermore, a three-plasmid reverse genetics system was applied to engineer a Pichinde virus (PICV) vector expressing HA and/or NP antigens [67]. The rP18tri vaccine elicited specific humoral and adaptive immune responses against HA and NP in mice and provided long-term protection against the PR8 lethal mouse-adapted influenza strain [68]. Newcastle disease virus (NDV) vectors have also been used for influenza virus vaccine development. Expression of the HA gene from the human influenza A/WSN/33 virus in a vector based on the NDV Hitchner B1 strain elicited potent humoral immune responses in immunized mice and protected mice from challenges with the influenza A/WSN/33 virus [69].

The baculovirus expression vector system (BEVS) has been applied for the production of the recombinant Influenza-Flublok Quadrivalent vaccine [70]. The vaccine contains the HA gene of four influenza virus strains: A/Hawaii/70/2019 (H1N1), A/Minnesota/41/2019 (an A/Hong Kong/45/2019-like virus) (H3N2), B/Washington/02/2019 and B/Phuket/3073/2013. It has been approved for vaccination against influenza A and B subtype viruses [71].

Among other viral vectors, measles virus (MV) particles expressing the HA gene from the influenza virus A Sapporo/107/2013 strain protected cotton rats against influenza virus challenges [72]. Moreover, VSV-H5N1 particles rendered mice 100% resistant to challenges with homologous H5 clade 1 but also with various H5 clade 2 strains [73]. In the case of saRNA vectors, 90% protection was achieved in mice after administration of only 10 µg of SFV-HA RNA [74]. In a phase I/II trial, strong antibody responses were obtained in 80% and 86% of individuals vaccinated with VEE-HA particles (AVX502) after one and two doses, respectively [75].

The design of next generation immunogens against a broad range of influenza virus strains has been supported by the application of the computationally optimized broadly reactive antigen (COBRA) methodology [76]. Alignment of HA and NA multilayered consensus sequences from multiple subtypes of influenza viruses allowed evaluation of protective immune responses in mice. Targeting H1, H2, H3, H5, H7, N1, and N2 proteins, vaccinated mice were protected against multiple influenza virus subtypes.

Finally, based on the success of applying mRNA-LNPs for COVID-19 vaccine development, mRNA-LNPs were engineered to express monovalent, trivalent, or quadrivalent (qIRV) formulations of the influenza virus A and B HA gene [77]. Durable functional antibody responses were achieved in mice and macaques. In phase I, the qIRV was well tolerated, and reactogenicity, HA inhibition and seroconversion were higher compared to the control vaccine QIV (Fluzone High-Dose Quadrivalent, Sanofi Pasteur) [78]. In phase III, the quadrivalent mRNA-HA vaccine showed a relative efficacy of 34.5% (95% CI 7.4 to 53.9%) and was statistically superior compared to a control vaccine [79].

COVID-19 vaccines

Obviously, the greatest attention of vaccine development has recently been dedicated to COVID-19 vaccines due to the onset of the pandemic. All possible approaches, including vaccines based on whole viruses, protein subunits, viral vectors, and nucleic acids, have been verified as previously described [2]. Therefore, only a brief summary is included below and in Table 1. Among whole virus-based approaches, the CoronaVac (Sinovac) vaccine showed 67.7% (95% CI, 35.9 to 83.7%) efficacy against symptomatic COVID-19 and 100% efficacy against hospitalization in phase III [12]. It was granted EUA in 54 countries in 2021 [13]. The inactivated BBIBP-CorV (Sinopharm) whole virus vaccine showed 78.1% (95% CI, 64.8 to 86.3%) vaccine efficacy in phase III [80] and was granted EUA in China in 2020 [81] and by the WHO in 2021 [82].

The COVAX-19 protein subunit vaccine comprising the extracellular domain (ECD) of the SARS-CoV-2 spike (S) protein and an adjuvant elicited strong humoral and cellular immune responses in mice and provided protection against challenges with SARS-CoV-2 in hamsters [83]. The robust immune responses of COVAX-19 were confirmed in phase II [84]. COVAX-19 showed reduced severity and disease rates in phase III [85]. The NVX-CoV2373 vaccine, consisting of the nanoparticle-encapsulated full-length SARS-CoV-2 S protein and the Matrix M1 adjuvant, protected rats and baboons from SARS-CoV-2 challenges [86]. NVX-CoV2373 demonstrated superior antibody and CD4+ T-cell responses compared to serum samples from COVID-19 patients in phase I/II [87]. In phase III, NVX-CoV2373 provided 76.3% (95% CI, 57.4 to 86.8%) efficacy against symptomatic COVID-19 and 100% (95% CI, 17.9 to 100.0%) efficacy against severe COVID-19 [88]. NVX-CoV2373 was granted conditional marketing authorization (CMA) in the EU in 2021 and in the UK in 2022 [89].

Although a variety of viral vectors have been utilized for COVID-19 vaccine development, the focus here is solely on adenoviruses and rhabdoviruses. The chimpanzee virus vector ChAdOx1 has been engineered to express the full-length SARS-CoV-2 S protein, leading to robust antibody responses and protection of macaques challenged with SARS-CoV-2 [90]. Furthermore, 62.1% (95% CI 41.0 to 75.7%) vaccine efficacy was obtained after two standard doses and 90.0% (95% CI 67.4 to 97.0%) after a low dose and a standard dose in phase III [8]. The ChAdOx1 nCoV-19 vaccine was granted EUA in the UK in 2020 [9]. Likewise, the Ad5-based Ad5-nCoV vaccine received EUA in China in 2021 [91]. Furthermore, the single dose Ad26.COV2.S vaccine demonstrated a 52.9% (95% CI, 47.1 to 58.1%) vaccine efficacy in phase III [92], and the FDA granted EUA in 2021 [93]. Alternatively, Ad vectors have been used for the expression of the SARS-CoV-2 S protein according to a prime-booster strategy, where the first vaccination with Ad26-S is followed by Ad5-S [94]. The Ad26-S/Ad5-S regimen (Sputnik V) showed a 91.6% (95% CI 85.6 to 95.2%) vaccine efficacy in phase III [95], and EUA was granted in Russia in 2020 [96].

VSV vectors expressing the SARS-CoV-2 S protein resulted in protection of BALB/c mice against SARS-CoV-2 challenges [97]. The VSV-SARS-CoV-2 S (V590) vaccine showed good safety and tolerability in phase I, but the inferior immune responses compared to sera from convalescent COVID-19 patients led to the termination of the trial [98]. Moreover, the SARS-CoV-2 S gene was introduced into the VSV vector replacing the VSV G protein, which elicited potent neutralizing antibodies in golden Syrian hamsters vaccinated with the chimeric VSV-∆G vector [99]. The VSV-∆G vaccine induced robust neutralizing antibody responses against SARS-CoV-2 in phase II [100].

Among DNA-based COVID-19 vaccines, the synthetic INO-4800 vaccine induced robust immune responses and neutralized SARS-CoV-2 in mice and guinea pigs [101]. In phase II, individuals who had at least 12 months earlier received two doses of INO-4800 were vaccinated with an INO-4800 booster dose of 1 or 2 mg [102]. Superior immunogenicity was obtained in vaccinees who received the higher dose. The ZyCoV-D DNA vaccine containing the SARS-CoV-2 S receptor binding domain (RBD) elicited neutralizing antibodies and T-helper1 (Th1)-biased responses in mice, guinea pigs, and rabbits [103]. Good safety and robust immune responses were obtained in phase I/II [104], and a 66.6% (95% CI 47.6 to 80.7%) vaccine efficacy was achieved in phase III [10]. ZyCoV-D was granted EUA in India in 2021 [11].

In the case of mRNA-based COVID-19 vaccines, the LNP encapsulated prefusion-stabilized full-length SARS-CoV-2 S RNA (BNT162b2) vaccine provided protection against SARS-CoV-2 challenges in immunized macaques [105]. A vaccine efficacy of 95% (95% CI, 90.3 to 97.6%) was obtained for the BNT162b2 vaccine in phase III [5]. EUA was granted for BNT162b2 in the EU and Switzerland in 2020 [6]. Another RNA-LNP vaccine, mRNA-1273, protected mice and primates against SARS-CoV-2 challenges [106]. In phase III, the mRNA-1273 vaccine showed a 94.1% (95% CI, 89.3 to 96.8%; p < 0.001) vaccine efficacy [107]. The FDA granted EUA for mRNA-1273 in 2020 [108].

The approach of developing saRNA-based COVID-19 vaccines resulted in superior mRNA quantities and the potential of using lower doses for immunization [109]. The VEE replicon-based LNP-nCoVsaRNA vaccine elicited strong antibody responses in mice [109]. The LNP-nCoVsaRNA vaccine showed good safety and tolerability in phase I, and although 100% seroconversion was not achieved, specific immune responses were elicited [110]. Superior seroconversion rates were seen in phase II by the prolongation of dosing intervals or by the administration of a 0.1 µg booster dose after two 1.0 µg doses [111]. The LUNAR-COV19 RNA LNP formulation showed 95% protection against severe COVID-19 and 55% overall protection against symptomatic disease in phase II [112]. The lipid inorganic nanoparticle (LION) formulation of VEE-SARS CoV-2 S RNA showed good safety and immunogenicity in a phase II/III trial [113]. EUA was granted to LION VEE-SARS CoV-2 S in India in 2025 [114].

Vaccine waning and emerging variants

Vaccinations against various infectious diseases have been characterized by a decrease of protection efficacy with time. There are two contributing reasons for the reduced vaccine efficacy and effectiveness: waning with time and emerging new variants of virus strains. Studies on influenza virus vaccines [115, 116] and mumps vaccines [117] have demonstrated waning. Simulation studies have also been conducted on vaccine efficacy, vaccine effectiveness, and waning [118]. Waning of humoral immunity was investigated for different types of COVID-19 vaccines three months post-vaccination in healthcare workers [119]. The study revealed that a two-dose homologous vaccination with the ChAdOx1 nCoV-19 vaccine or homologous mRNA-1273 booster vaccinations induced more durable immune responses than two-dose homologous mRNA vaccinations, homologous BNT162b2 booster vaccinations, or two-dose ChAdOx1 nCoV-19 vaccinations followed by a BNT162b2 booster vaccination. In a systematic review and meta-analysis, a decrease in protection against SARS-CoV-2 infection decreased by 21.0% over a six-month period in individuals of all ages receiving full vaccination [120]. There was no difference between vaccinations with the BNT162b2, mRNA-1273, Ad26.COV2.S and ChAdOx1 nCoV-19 vaccines. Vaccine effectiveness was reduced by only 10% for severe disease and remained higher than 70% for six months.

Emerging and re-emerging viral strains and variants play an important role in the decrease in the efficacy and the effectiveness seen for a number of viral vaccines. The classic example of reduced vaccine effectiveness relates to the ever-changing surface structure of influenza viruses due to emerging variations in epitopes of the HA and NA proteins, the main targets for antigen development against influenza viruses [121]. Likewise, the SARS-CoV-2 S protein epitopes comprise the antigens of choice for COVID-19 vaccines [122]. To limit the length of this section, the focus here is solely on emerging variants of SARS-CoV-2 and their impact on the efficacy and the effectiveness of COVID-19 vaccines. Detailed studies on emerging variants have classified them as variants of concern (VoC), variants of interest (VoI), and variants under monitoring (VuM) [123]. Today, a long list of SARS-CoV-2 variants, including alpha, beta, delta, gamma, omicron, and recent subvariants of omicron, has been discovered [124]. However, due to the large number of published studies on SARS-CoV-2 variants and their impact on vaccine efficacy and effectiveness already reviewed [2, 125], a brief summary is presented below, and examples are listed in Table 2. In the case of whole virus-based vaccines, homologous and heterologous booster vaccinations with the ChAdOx1 nCoV-19 vaccine improved vaccine efficacy against delta and omicron variants [126]. In another study, individuals previously vaccinated with Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines received booster vaccinations with the NVX-CoV2373 protein subunit vaccine, which showed high pseudovirus-neutralizing antibody (PsVNA) responses against the D614G variant and low responses against the omicron BQ.1.1 and XBB.1 variants [127].

Among viral vector-based vaccines, the ChAdOx1 nCoV-19 vaccine did not manage to provide protection against the beta variant measured by pseudovirus and live-virus neutralization assays [128]. In another study, the ChAdOx1 nCoV-19 vaccine or the BNT162b2 mRNA vaccine was evaluated for SARS-CoV-2 transmission of the alpha and delta variants [129]. The transmission was inferior for the delta variant compared to the alpha variant. Moreover, higher reduction in transmission was obtained for the mRNA-based vaccine. A reduction of neutralizing antibody responses after a single administration of the Ad26.COV2.S vaccine was observed for the beta and gamma variants compared to the original SARS-CoV-2 strain [130]. Moreover, the durability of the vaccine efficacy of Ad26.COV2.S against the delta variant was at least six months [131].

The DNA-based INO-4800 vaccine elicited comparable levels of neutralizing antibodies for the gamma variant and the original SARS-CoV-2 strain [132]. Moreover, 2.1- and 6.9-fold reductions of neutralizing antibodies were obtained for the alpha and beta variants, respectively. To address SARS-CoV-2 variants, the next-generation INO-4802 was designed to target RBD and 2P mutations, resulting in potent neutralizing antibody and T-cell responses against the original SARS-CoV-2 strain and the alpha, beta, and gamma variants [133]. Immunization experiments in macaques showed improved neutralizing and ACE2 blocking activity for both the variants and the original strain.

In the case of mRNA-based vaccines, the BNT162b2 vaccine effectiveness against the delta variant was 68% (95% CI, 48 to 80%) in Spain [134] and 90% (95% CI, 84 to 94%) in the UK [135]. The vaccine effectiveness against the omicron BA.1 and BA.2 variants was 63% (95% CI, 58 to 67%) in the US [136], 30% (95% CI, 9 to 55%) in Israel [137], and 49.4% (95% CI, 47.1 to 51.6%) in Qatar [138]. In the context of the mRNA-1273 vaccine, the alpha variant showed a 1.2-fold decrease in neutralizing antibody titers compared to the D614G strain and a 2.1- to 8.4-fold reduction in titers for the beta, gamma, and delta variants [139]. Certain mRNA-based vaccines have also been subjected to re-engineering efforts to improve the immunogenicity against emerging variants. For example, the bivalent mRNA-1273.214 was designed to contain the original mRNA-1273 and the corresponding RNA for the omicron BA.1 variant [140]. The bivalent vaccine elicited higher neutralizing antibody titers against omicron and also induced higher binding activity against the alpha, beta, gamma, and delta variants than the mRNA-1273 vaccine in a phase II/III study [140]. Booster vaccination with the updated mRNA XBB.1.5 vaccine induced 27-fold enhanced neutralizing antibody titers against the omicron XBB.1.5 and EG5.1 variants and also against other emerging viruses such as HV.1, HK.3, JD.1.1, and JN.1 [141]. Among saRNA-based vaccines, strong immune responses and protection of hamsters against D614G and alpha variant challenges were obtained for the LNP-nCoVsaRNA vaccine [142].