Prompetchara, Eakachai, et al. “Immune Responses in COVID-19 and Potential Vaccines: Lessons Learned from SARS and MERS Epidemic.” Asian Pacific Journal of Allergy and Immunology, vol. 38, 2020, pp. 1–9., doi:10.12932/ap-200220-0772.

https://apjai-journal.org/wp-content/uploads/2020/03/1.pdf?fbclid=IwAR1kVlFnoc6mobqEy7FDz_93fX__AaY8ZgE4TUwtjzhh8oVqgs82rgf3QoU

Immune Responses in COVID-19 and Potential Vaccines: Lessons Learned from SARS and MERS Epidemic

The SARS-CoV-2 virus infects type 2 alveolar cells with the ACE2 receptor in the lung. The virus may suppress anti-viral IFN, leading to viral replication, causing increased neutrophils and macrophages and over-production of pro-inflammatory cytokines. Also, Th1/Th17 might be activated, increasing the inflammatory response. The B cells and plasma cells produce SARS-CoV-2 specific antibodies. 


Innate Immune Response to SARS-CoV-2 Summary

Due to the likeness between SARS-CoV-2 and other betacoronaviruses, it is likely that target antigen selection and vaccine platform have been based on SARS-CoV and MERS-CoV. The full-length spike or S1 (which contains receptor binding domains) that is employed in DNA, viral vector, and subunit vaccines show promise because they have induced neutralizing antibodies in clinical and preclinical studies of SARS-CoV and MERS-CoV, with the DNA vaccine making the most advancement in clinical trials. 

Prophylactic Vaccines

- Coronaviruses have adapted to evade immune detection and dampen the human immune responses. This is why they have a 2-11 days incubation period that is longer than influenza
- SARS-CoV-2 may do this in a way similar to MERS and SARS-CoV. From current knowledge, coronaviruses interfere with: RNA sensing, the signaling pathway of type I IFN production, and as a result Stat 1/2 activation 
- The process of adaptive immune evasion in SARS-CoV-2 may be similar to the process that occurs in MERS. When macrophages were infected with MERS, there was less antigen presentation through MHC class I and II.

Potential Immune Evasion Mechanisms

Information gained from studies done on both the immune response and vaccine development to related betacoronaviruses can help us gain insight on the immunopathology of SARS-CoV-2 and guide the devlopment of a vaccine. 

Smith College

Carnegie Mellon University

Virus vaccines use the virus itself, or  in a weakened or inactive form.

Virus Vaccines for COVID-19

Nucleic Acid Vaccines use genetic material (DNA/RNA) from a viral protein that induces an immune response. The nucleic acid is inserted into human cells, which create copies of the virus protein. For many COVID-19 vaccines in development, the nucleic acid codes for the virus's spike protein. Both DNA and RNA vaccines trigger CD8+ cytotoxic T cell response to eradicate virus, in addition to antibody and CD4+ T cell responses.
However, because of their remarkable risk of failure, not a single nucleic acid vaccine has ever been licensed.

Some types of nucleic acid vaccines include (image):

Nucleic Acid Vaccines for COVID-19

Viral-Vector vaccines genetically engineer another virus, referred to as vectors, to carry genetic materials from the coronavirus and produce coronavirus proteins in the human body. These vectors are weakened and does not cause disease. Two main types are (shown in image):

Viral-Vector Vaccines for COVID-19

Unlike traditional vaccine, an mRNA vaccine is an mRNA sequence that encodes a specific disease antigen. When the mRNA vaccine enters cells, the antigen gets expressed in the immune system and a strong T-cell response is produced. mRNA vaccines claim to be efficient and less expensive to produce.

mRNA Vaccines for SARS-CoV-2


Protein-based vaccines inject coronavirus proteins directly into the body to stimulate an immune response. Alternatively, fragments of proteins or protein shells that mimic the coronavirus' outer coat is also being tested. 

Protein Subunit and Virus-Like Particle Vaccines for COVID-19

Vaccine Development for SARS-CoV-2 Based on Knowledge Gained from SARS-CoV and MERS-CoV

Live-attenuated vaccines (LAVs) are live, reproducing, yet mild viruses. The designs are meant to produce single-dose immunity without illness. 


Live-attenuated vaccines

IVs are pathogens (or fractions thereof) that have been inactivated by heat or chemical reaction

Inactivated vaccines (IVs)

- mRNA-1273 (NCT04405076) Vaccine 
- BNT162b1/BNT162b2/BNT162b3 (NCT04368728) Vaccines
- INO-4800 (NCT04336410) Vaccine
- NCT04334980 Vaccine

Nucleic Acid Vaccines in Clinical Trial for COVID-19

Nanomaterials have emerged as promising tools to amplify or suppress host's immune response. By acting as adjuvants added to vaccines for COVID-19, engineered nanomaterials can aid subjects with impaired immune system, such as the elderly, and reduce the amount of vaccine protein production and injection. 


Intranasal delivery of polymer-encapsulated antigen triggers a strong immune response, and the success of vaccination depends on the appropriate type of polymer in combination with the antigen. Similarly, researchers have developed lipid and lipid-based NPs as delivery platforms for mRNAs or siRNAs to enable the synthesis of key viral proteins for vaccination (for example, Moderna’s mRNA-1273/NCT04283461 vaccine) or to inactivate critical viral target genes, respectively. 


Considering the possibility of random viral mutations that may alter the antigen shape, functionalizing nanomaterials with a wide number of molecules at the same time to target the virus, or motifs that are specific for pathogens, will increase the efficiency of vaccines and their ability to prevent viral infection.


There are ongoing screenings and classifications of various nanomaterials based on their immunomodulatory properties and cytotoxicity levels. Developing an adjuvant for clinical use requires Phase III randomized trials, which could take several years.


Nanomaterial-based Immune Modulation for SARS-CoV-2

- DNA vaccines have higher stability than mRNA vaccines
- the non-integrating feature of mRNA prevents insertional mutagenesis
- mRNA half-life, stability, and immunogenicity can be modified


DNA vaccines vs RNA vaccines

A self-amplifying RNA (saRNA) vaccine typically consists of a saRNA encapsulated in lipid nanoparticles. This type of vaccine is useful to combat a global pandemic, as it is able to encode any antigen of interest and requires less dosage compared to an mRNA vaccine. 

Self-amplifying RNA vaccine

- Using Ad5 by CanSino Biologics
- Using Chimpanzee adenovirus  (ChAdOx1 nCoV-19) by The University of Oxford
- Using Ad26 by Johnson & Johnson
- Using NCT04276896/NCT04299724 by Shenzhen Geno-Immune Medical Institute

Viral-Vector Vaccines in Clinical Trial for COVID-19

- A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2

Viral-Vector Vaccines in Animal Studies for COVID-19

The antibody and T cell responses of both the upper and lower-airway challenges were recorded before and after administration of the vaccine. The vaccine candidates were able to produce higher antibody levels than convalescent-phase human serum. Th1 responses were induced in all vaccine candidates and negligible Th2 responses were observed. Viral replication was eliminated in the nose and limited in the lungs of the vaccine candidates. This vaccine provided rapid protection and neutralizing activity in the upper and lower airways without damaging the tissues. Because nonhuman primates and humans are similar in nose and lung environments and it is assumed that a vaccine that performs will in primates will produce similar effects in humans. This information was used to determine that mRNA-1273 vaccines were ready for Phase 1 human trials. The active was published in July and updated in August 2020.

mRNA-1273 Vaccine Trials in Nonhuman Primates

As of October 14th, a trial was done consisting of randomly selected healthy adult 18-55 years old and 65-85 years of age to receive the placebo or the RNA vaccine.  "Two lipid nanoparticle–formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor–binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation."

Results: 
Each group at 15 participants where 12 received the vaccine and 3 received the placebo. BNT162b2 resulted in lower incidence and a severity in systemic reactions. 

The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates consisting of people of a range of ages, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2–3 safety and efficacy evaluation.

Reference (was not adding as a node so was added to here): Walsh, Edward E., et al.Â Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates: NEJM. 8 Oct. 2020, www.nejm.org/doi/full/10.1056/NEJMoa2027906?query=featured_coronavirus.Â

Phase 1 of trying RNA-based vaccine as of October 14th, 2020

Protein-Based Vaccines in Clinical Trials for COVID-19

These are two methods of processing and presenting antigens to human body.

Nanocarriers need to be degraded for encapsulated antigens to trigger cellular immune response, while the surface displayed antigens primarily lead to humoral immune response. 

encapsulated antigen vs surface displayed antigens

- La Jolla Institute for Immunology (LJI) 
- University of Cambridge/DIOSynVax
- Immunonomic Therapeutics/EpiVax/PharmaJet

Learn Before

Related

Learn After