From Smallpox to COVID-19, a Flexible Vaccinia Virus-based Platform to Prevent Diseases

Despite the difficulties that certain countries are experiencing during the implementation of an effective vaccination strategy, the global SARS-CoV-2 pandemic has led to a collective effort for the generation of effective and safety vaccines in a very short time. At present there are a large number of vaccine candidates based either on the whole virus (inactivated or attenuated), non-replicating viral vectors expressing viral antigens, mRNA or DNA-based vaccines, and other that use viral subunits such as proteins or virus-like particles [1, 2]. Most of the vaccines are based on SARS-CoV-2 spike (S) protein expression, as it mediates the virus cell entry through binding to its host receptor, the angiotensin-converting enzyme 2 (hACE2), being also the main target for neutralizing antibodies (nAbs) [3]. 

Proposed vaccine platforms to fights against SARS-CoV-2. Tregoning JS, et al. Vaccines for COVID-19. Clin Exp Immunol. 2020 Nov;202(2):162-192. doi: 10.1111/cei.13517.

Vaccines must fulfil the safety requirements of the corresponding drug agencies and achieve highly protective and durable responses. Although in December 2020 two candidate mRNA vaccines (from Pfizer-BioNTech and Moderna) have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for emergency human use, another promising candidate is based on the vaccinia virus (VACV), a vector that served to eradicate smallpox [4]. Highly attenuated VACV strains like modified Ankara (MVA) have been produced and shown to be an excellent vector to generate efficacious vaccines against a variety of pathogens [5] due to its safety record, stability, long-term immune responses and ability to incorporate large fragments of foreign genetic material. MVA-based vaccine candidates for emerging viruses such as Chikungunya [6], Zika [7] and Ebolavirus [8] have been shown to be highly immunogenic in animal models, inducing pathogen-specific T cell responses and nAbs, and providing protection against infection with just one single dose.

Published in Journal of Virology [9], García-Arriaza, J, et al. from the Spanish National Center of Biotechnology (CNB-CSIC) described the development of two vaccine candidates based on MVA vectors expressing the full-length SARS-CoV-2 spike (S) protein. The first candidate was based on the attenuated wild-type MVA (MVA-S), whereas the second used an MVA lacking the VACV immunomodulatory genes (MVA-Δ-S), which is supposed to increase the immune response against vaccine antigens. To assess the immunogenicity elicited by MVA-S and MVA Δ-S, the authors followed an heterologous DNA/MVA or homologous MVA/MVA prime/boost immunization regimes, as they were described to be more immunogenic and superior in efficacy than immunizations with one single dose. During the heterologous protocol, mice received 100 µg of DNA-S prime by intramuscular (i.m) route, and 15 days later were boosted with MVA-S or MVA-Δ-S by i.m route. During the homologous protocols, mice were immunized similarly with two doses of MVA-S or MVA-Δ-S. In both cases the MVA-WT vector was used as a control group. 

Magnitude of total S-specific T cell immune response. García-Arriaza J, et al. COVID-19 vaccine candidates based on modified VACV Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice. J Virol. 2021 Jan 7:JVI.02260-20. doi: 10.1128/JVI.02260-20.

All MVA-S and MVA-Δ-S vaccinated groups induced significant high levels of interferon gamma (IFN-γ)-secreting cells against viral S protein, being the DNA-S/MVA-Δ-S the one with the highest levels. Analysis of the induction of specific CD4+ and CD8+ T cells expressing CD107a (which indicates the cytotoxic potential), IFN-γ, tumor necrosis factor alpha (TNF-α) and/or interleukin-2 (IL-2) demonstrated that all vaccinated groups elicited robust S-specific T cell responses, being greater in heterologous DNA/MVA than in homologous MVA/MVA regimens with a higher overall response in the CD8+ T cell repertoire, and reflecting a CD4+ Th1 profile. Furthermore, S-specific CD4+ T cells induced by DNA-S/MVA-S were significantly higher than those induced by the DNA S/MVA Δ-S group, but were similar between the homologous groups. In all cases boosting with MVA-Δ-S elicited significantly higher levels of S-specific CD8+ T cells than with MVA-S in both prime/boost regimens. Surface markers of memory T cells showed that, in all vaccinated groups, S-specific CD4+ and CD8+ T cells were mainly of the T effector memory (Tem) phenotype. Moreover, al vaccination regimes generated S-specific CD8+ T resident-like memory cells secreting IFN-γ. Heterologous DNA-S/MVA-Δ-S induced significant higher magnitude of S-specific CD8+ T resident-like memory cells than DNA-S/MVA-S or the homologous MVA-S/MVA-S immunizations. 

Memory phenotypic profiles of the S-specific CD4+ and CD8+ T cells. Percentages or naïve, T central memory (Tcm), T effector memory (Tem) and T effector (Te) cells were measured after every vaccination strategy. García-Arriaza J, et al. COVID-19 vaccine candidates based on modified VACV Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice. J Virol. 2021 Jan 7:JVI.02260-20. doi: 10.1128/JVI.02260-20.

One of the most important features of a good vaccine is that it should induce the production of nAbs against the S protein to control the COVID-19 progression. To assess the ability of the MVA-S vaccine candidates to elicit humoral responses, authors determined the presence of S- and receptor binding domain (RBD)-specific immunoglobulin Gs (IgGs) in the serum of immunized mice. All vaccinated groups induced high IgG2c titers against the S and RBD proteins, confirming the polarization towards Th1-like immune responses previously described. 

Individual serum samples obtained from all mice vaccinated with MVA-S or MVA-Δ-S neutralized the S-pseudotyped particles in vitro, compared with the serum of the control group, being the serum from homologous MVA-S/MVA-S the most active. 

Finally, authors wanted to assess the efficacy of the MVA-S vaccine in K18-hACE2 mice, a mouse model in which the hACE2 is expressed, representing a model for SARS-CoV-2 infection and lethality. All the K18-hACE2 mice immunized with two doses of MVA-S and challenged with SARS-CoV-2 did not show loss of body weight and survived, whereas the MVA WT or non-immunized and challenged K18-hACE2 mice showed more than 25% loss of body weight and died within 6 days post-challenge. Mice immunized with one single dose of MVA-S and challenged with SARS-CoV-2 lost body weight during the first days post challenge, but they recover at day four and finally survived, demonstrating that one single dose could be enough to ameliorate the effects of the disease. 

MVA-S vaccine protects K18-hACE2 mice from SARS-CoV-2 infection. Upper row: Immunization schedule of different groups tested. Bottom row: Authors measured the body weight (left) and % survival (right) after viral challenge in every group. García-Arriaza J, et al. COVID-19 vaccine candidates based on modified VACV Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice. J Virol. 2021 Jan 7:JVI.02260-20. doi: 10.1128/JVI.02260-20.

As SARS-CoV-2 replication was completely prevented at days two and four post challenge in animals that received two doses of MVA-S, compared to the controls, and given that a single dose of MVA-S has also a major effect avoiding viral replication, the MVA vaccine candidate seems to be highly efficacious to control the SARS-CoV-2 morbidity, lethality and replication in a mouse model of infection. 

The MVA vaccine candidate is still on its development phase, and still need to enter clinical trials before its approval and validation by the Regulatory Agencies. The two mRNA vaccines approved by the FDA for emergency human achieved 90-95% efficacy in protection against COVID-19 in humans [10, 11], generating significant neutralizing antibody titers and virus-specific T cell responses 2-4 weeks post inoculation [12, 13]. The main advantage of mRNA vaccines is that they can be easily update with new sequences targeting different parts of the viral structure, and the construction of the lipid nanoparticles that contains the mRNA sequence is a wise-optimized procedure. The simplicity of their design favors a specific response against the viral immunogen. On the other hand, the MVA vaccine is made from a modified vaccinia virus, being possible that the epitopes expressed by the carrier viral particle could interfere with the immune response against the SARS-CoV-2 antigen. Although a direct comparison between mice and human immunization data is not possible, the MVA-based vaccine seems to be highly specific following mouse administration, and the clinical behavior could be similar to the adenoviral-based vaccines. 

Undoubtedly, the use of a modified VACV will be a good strategy for the future development of vaccines against the SARS-CoV-2 and other viral pathogens. In the meanwhile, both Regulatory Agencies and Governments must ensure that once developed, produced and put into circulation, vaccines can be correctly administered and reach the end users, who are all of us.


1. Funk, C.D., C. Laferriere, and A. Ardakani, A Snapshot of the Global Race for Vaccines Targeting SARS-CoV-2 and the COVID-19 Pandemic. Front Pharmacol, 2020. 11: p. 937.

2. Amanat, F. and F. Krammer, SARS-CoV-2 Vaccines: Status Report. Immunity, 2020. 52(4): p. 583-589.

3. Addetia, A., et al., Neutralizing Antibodies Correlate with Protection from SARS-CoV-2 in Humans during a Fishery Vessel Outbreak with a High Attack Rate. J Clin Microbiol, 2020. 58(11).

4. Mayr, A., Smallpox vaccination and bioterrorism with pox viruses. Comp Immunol Microbiol Infect Dis, 2003. 26(5-6): p. 423-30.

5. Volz, A. and G. Sutter, Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development. Advances in virus research, 2017. 97: p. 187-243.

6. Roques, P., et al., Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus. JCI Insight, 2017. 2(6): p. e83527.

7. Perez, P., et al., A Vaccine Based on a Modified Vaccinia Virus Ankara Vector Expressing Zika Virus Structural Proteins Controls Zika Virus Replication in Mice. Sci Rep, 2018. 8(1): p. 17385.

8. Lazaro-Frias, A., et al., Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins. J Virol, 2018. 92(11).

9. Garcia-Arriaza, J., et al., COVID-19 vaccine candidates based on modified vaccinia virus Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice. J Virol, 2021.

10. Polack, F.P., et al., Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med, 2020. 383(27): p. 2603-2615.

11. Baden, L.R., et al., Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med, 2021. 384(5): p. 403-416.

12. Widge, A.T., et al., Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination. N Engl J Med, 2021. 384(1): p. 80-82.

13. Sahin, U., et al., COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature, 2020. 586(7830): p. 594-599.

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