Adenovirus Vaccines (application for Covid-19)

1. -Potential advantages of Adenovirus vaccines over conventional vaccines

1.1. Adenoviruses provide us with a robust method of delivering vaccinations due to their adaptable genome and their ability to induce a high immune response. As discussed by Privatt, S., et. al. in their longitudinal study of adenovirus vaccines (doi: 10.1016/j.vaccine.2019.07.074 ), there are certain serotypes of the adenovirus which are malleable and provide excellent vectors for vaccination of a specific disease, while also potentially providing protection from adenovirus itself. These factors would allow us to overcome production barriers and reduce cost, which would make vaccinations available to the most needed areas of the world.

1.1.1. Longitudinal quantification of adenovirus neutralizing responses in Zambian mother-infant pairs: Impact of HIV-1 infection and its treatment - PubMed

2. -Characteristics of the Adenovirus vaccines in development against Covid-19 (Sars-cov-2 virus)

2.1. Using adenoviruses as a vector for vaccination has a high potential due to its ability to drive high humoral and cellular adaptive immune responses. The recent increase in research using adenoviruses as a potential vector proves to be an exciting area of research in this time of desperate need for a vaccine agains COVID-19 (SARS-CoV-2).

2.1.1. Prospects of Replication-Deficient Adenovirus Based Vaccine Development against SARS-CoV-2

2.2. Evidence shows that taking advantage of the benefits adenoviruses provide in vaccine production proves to be an effective vaccine against COVID-19 (SARS-CoV-2).

2.2.1. https://www.nature.com/articles/s41467-020-17972-1

3. -Most common adverse effects of Adenovirus vaccine that have been reported within 14 days after vaccination in phase 2 clinical trial (application for Covid-19)

3.1. Injection site adverse reactions

3.1.1. pain, induration, redness, swelling, and itching.

3.2. Systemic adverse reactions

3.2.1. fever, headache, fatigue, vomiting, muscle pain, diarrhea, joint pain, cough, nausea, and hypersensitivity.

3.3. Zhu, Feng-Cai et al. “Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.” Lancet (London, England) vol. 396,10249 (2020): 479-488. doi:10.1016/S0140-6736(20)31605-6

4. -Expected timeline for developing an approved Adenovirus vaccine in development against COVID-19

4.1. There is still no specific timeline for developing an approved Adenovirus vaccine. However, the WHO is facilitating collaboration and efforts to support vaccine development by defining the desired characteristics of promising candidate vaccines to combat COVID-19. This situation emphasizes the importance of being prepared to start an international multicentre, randomized, double-blind, controlled phase 3 effectiveness trial as soon as possible.

4.2. Zhu, Feng-Cai et al. “Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.” Lancet (London, England) vol. 396,10249 (2020): 479-488. doi:10.1016/S0140-6736(20)31605-6

5. Routes of inoculation

5.1. Oral

5.1.1. Currently, the adenovirus vaccine comes as 2 tablets taken orally at the same time which contain live adenovirus Type 4 and Type 7. They should be swallowed whole, not chewed or crushed.

5.1.2. Vaccine Information Statement. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/hcp/vis/vis-statements/adenovirus.html. Published January 8, 2020.

5.2. IM injection

5.2.1. The mRNA-1273 vaccine in development is an IM sterile liquid injection administered in the deltoid muscle, but it has not been approved yet.

6. -Background about the use of Adenovirus for creating vaccines

6.1. At first, adenovirus vectors were used for gene therapy but were largely unsuccessful in this area. Adenoviruses are seen as great vectors for vaccines as they can delivery target antigens by inducing both innate and adaptive immune systems. Adenovirus vectors are currently being explored in the use of vaccines ranging from malaria to HIV and also tumor associated antigens. As vectors for vaccines, they are relatively large and have a well characterized genome which allows adenoviruses to be easily genetically manipulated.

6.1.1. Tatsis, N., & Ertl, H. C. (2004). Adenoviruses as vaccine vectors. Molecular therapy : the journal of the American Society of Gene Therapy, 10(4), 616–629. Redirecting

6.1.2. What are Adenovirus-Based Vaccines?

7. Examples of Adenovirus vaccines in development

7.1. Many COVID-19 vaccines are currently in different stages of development.

7.1.1. Currently in clinical trials is the heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S).

7.1.2. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020;396(10255):887-897. doi:10.1016/S0140-6736(20)31866-3

7.1.3. Another vaccine is the mRNA-1273 vaccine candidate, manufactured by Moderna. It encodes the S-2P antigen, consisting of the SARS-CoV-2 glycoprotein with a transmembrane anchor and an intact S1–S2 cleavage site.

7.1.4. Jackson LA, Al. E, Group* for the mRNA-1273 S, et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report: NEJM. https://www.nejm.org/doi/full/10.1056/nejmoa2022483. Published November 12, 2020.

8. -Genetic elements of Adenovirus vaccines, types of viruses that are currently used

8.1. Adenoviruses express 2 types of genetic components: early and late genes. Early genes are responsible for viral replication in host cells while late genes are responsible for host cell lysis and viral assembly. The E1 gene, an early gene, has been manipulated through deletion within adenoviruses to prevent the virus from growing in numbers when infecting its host. The types of viruses that are being used are HIV, influenza, ebola, rabies, etc. Adenovirus vaccines are made through the insertion of transgene cassette into the backbone of the virus where the transgene cassette expresses the target antigen.

8.1.1. Tatsis, N., & Ertl, H. C. (2004). Adenoviruses as vaccine vectors. Molecular therapy : the journal of the American Society of Gene Therapy, 10(4), 616–629. Redirecting

8.1.2. https://www.news-medical.net/health/What-are-Adenovirus-Based-Vaccines.aspx

8.1.3. Tanu Chawla, Navin Khanna & Sathyamangalam Swaminathan (2008) Adenovirus-vectored vaccines, Expert Opinion on Therapeutic Patents, 18:3, 293-307, DOI: 10.1517/13543776.18.3.293

9. Expression of antigens induced by adenovirus vaccine

9.1. According to a study from the Elsevier public health emergency collection, adenoviral vectors persist at low levels and therefore, induce both sustained effector-like and central memory T cell responses. Analyses of vaccine-induced immune responses showed that in a dose-dependent manner, vaccine recipients developed T and B cells to the transgene product. They also had increases in immune responses to antigens of the adenoviral vector.

9.2. Ertl HCJ. Adenoviral Vector Vaccines Antigen Transgene. Adenoviral Vector Vaccines Antigen Transgene Published 2016.

10. -Background information about the phase 2 clinical trial participants and reported adverse reactions that are associated with the Covid-19 vaccine

10.1. Within 14 days after the vaccination, 183 (72%) of 253 participants in the 1 × 1011 viral particles dose group, and 96 (74%) of 129 participants in the 5 × 1010 viral particles dose group reported at least one solicited adverse reaction, both of which were significantly higher than the 46 (37%) of 126 participants in the placebo group (p<0·0001) https://doi.org/10.1016/S0140-6736(20)31605-6

11. Initial results of treating animal models with Adenovirus vaccines against Covid-19

11.1. Recent studies show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike the (S) protein in non-human primates.

11.2. 52 rhesus macaques (a type of monkey) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes

11.3. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge.

11.4. Titers of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection.

11.5. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates.

11.6. The optimal Ad26 vector-based vaccine for SARS-CoV-2 is now being evaluated in clinical trials

11.7. Mercado NB, Zahn R, Wegmann F, et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature. 2020;586(7830):583-588. doi:10.1038/s41586-020-2607-z

12. Initial results of using Adenovirus vaccines in human clinical trials

12.1. safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine has been assessed and expresses the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.

12.2. Phase I was tried on patients in Wuhan, China receiving an IM injection of 1of 3 different doses

12.3. The primary outcome was adverse events in the 7 days post-vaccination.

12.4. Specific Antibodies were also detected using ELISA detection method 28 days post-vaccination

12.5. Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020;395(10240):1845-1854. doi:10.1016/S0140-6736(20)31208-3