Wednesday, May 13, 2020



Dr K K Aggarwal
President Confederation of Medical Associations of Asia and Oceania, HCFI, Past National President IMA, Chief Editor Medtalks

With inputs from Dr N K Ganguly, Dr Rajan Sharma, Dr RV Asokan

841: Coronavirus vaccines


1.      Coronaviruses: Virus, Spike protein; Envelope, Membrane, RNA, Nucleic
2.      Difficulties: Virus behaves like HIV, cause immune inflammation, causes cytokine storm, causes thrombo-inflammatory reactions, bring down immunity and has latency
3.      Immunity: Short term or long term; Booster doses, immunity lasting one year,
4.      Herd Immunity Threshold: R-1/R, Protecting older people, Disabled people, immunocompromised people.
5.      Development Time ong: Pre clinical studies 3 months, small phase I study for safety, medium size phase II study, formulation, dose, safety immunogenicity and reactogenicity, large phase III efficacy
6.      Because people have no immunity to COVID-19, it's likely that two shots will be needed, three to four weeks apart. People would likely start to achieve immunity to COVID-19 one week after the first vaccination and large boost after the second dose.
7.      There are 120 vaccine initiative around the world. Virus vaccines (Live attenuated or inactivated): At least seven teams are developing vaccines using the virus itself, in a weakened or inactivated form. Sinovac Biotech in Beijing has started to test an inactivated version of SARS-CoV-2 in humans. The inactivated version will also be developed in the Serum Institute.
8.      Viral-vector vaccines (Replicating or non replicating) : The following platforms are being used: Measles, Chimp adenovirus, Adenovirus 26, Pox virus vectors etc.
9.       Nucleic-acid vaccines: (in the form of DNA or RNA) for a coronavirus protein that prompts an immune response. The nucleic acid is inserted into human cells, which then churn out copies of the virus protein; most of these vaccines encode the virus’s spike protein
10.   Protein-based vaccines: Many researchers want to inject coronavirus proteins directly into the body. Fragments of proteins or protein shells with adjuvants that mimic the coronavirus’s outer coat can also be used. ( virus subunit or virus like particle)

Vaccine Types

Live attenuated: Radiation, heat, chemicals; harmless virus; MMR, smallpox and chickenpox; weak immunity

To date, live attenuated vaccines for COVID virus has not been evaluated. Systems have been developed to generate cDNAs encoding the genomes of CoVs, including SARS-CoV. The panel of cDNAs spanning the entire CoV genome can be systematically and directionally assembled by in vitro ligation into a genome-length cDNA from which recombinant virus can be rescued. This system has been used for genetic analysis of SARS-CoV protein functions and will enable researchers to engineer specific attenuating mutations or modifications into the genome of the virus to develop live attenuated vaccines.

While live attenuated vaccines targeting respiratory viruses, including influenza viruses and adenoviruses, have been approved for use in humans, the observation that infectious virus is shed in the feces of SARS-CoV-infected individuals raises concerns that a live attenuated SARS-CoV vaccine strain may also be shed in feces, with potential to spread to unvaccinated individuals. Another concern is the risk of recombination of a live attenuated vaccine virus with wild-type CoV; however, there may be ways to engineer the genome of the vaccine virus to minimize this risk. [Codagenix/Serum Institute of India]

Killed inactivated vaccines, flu, polio, hepatitis A, B, tetanus, whooping cough and rabies. Multiple doses, Booster, require large dose to prepare

The immunogenicity and efficacy of inactivated SARS-CoV vaccines have been established in experimental animals, and one such vaccine is being evaluated in a clinical trial. However, the development of inactivated vaccines requires the propagation of high titers of infectious virus, which in the case of SARS-CoV requires biosafety level 3-enhanced precautions and is a safety concern for production. Additionally, incomplete inactivation of the vaccine virus presents a potential public health threat. Production workers are at risk for infection during handling of concentrated live SARS-CoV, incomplete virus inactivation may cause SARS outbreaks among the vaccinated populations, and some viral proteins may induce harmful immune or inflammatory responses, even causing SARS-like diseases

Genetically engineered: RNA or DNA that has instructions for making copies of the S protein. These copies prompt an immune response to the virus. With this approach, no infectious virus needs to be handled. None has been licensed for human use.

DNA vaccines have demonstrated strong induction of immune responses to viral pathogens in animal models, specifically in mice; however, clinical data on DNA vaccines in human subjects are limited. DNA vaccines encoding the S, N, M, and E proteins of SARS-CoV have been evaluated in mice. Vaccination with S-, M-, and N-encoding DNA vaccines induced both humoral and cellular immune responses, with some variation in the relative levels of induction.

S protein in receptor binding and membrane fusion indicate that vaccines based on the S protein could induce antibodies to block virus binding and fusion or neutralize virus infection. Among all structural proteins of SARS-CoV, S protein is the main antigenic component that is responsible for inducing host immune responses, neutralizing antibodies and/or protective immunity against virus infection. S protein has therefore been selected as an important target for vaccine and anti-viral development.

Although full-length S protein-based SARS vaccines can induce neutralizing antibody responses against the  responses against SARS-CoV infection, they canalso induce harmful immune responses against host or enhanced infection after challenge with homologous SARS-CoV, raising concerns about the safety and ultimate protective efficacy of vaccines that contain the full-length SARS-CoV S protein.

The gene-based vaccines: Contain pure genetic information in the form of coronavirus DNA or mRNA. Individual parts of genetic information from the pathogen are packed into nanoparticles and introduced into cells. Once the vaccine is in the body, it should form harmless viral proteins that build up immune protection. Vaccines are in development. The first vaccine to have completed Phase I made by moderna vaccine in USA.

Vectored Vaccines: Utilizing other viruses as vectors for SARS-CoV proteins, including a chimeric parainfluenza virus, MVA, rabies virus, vesicular stomatitis virus (VSV), and adenoviruses. Chimeric bovine/human parainfluenza virus 3 (BHPIV3), a live attenuated parainfluenza virus vaccine candidate, was utilized as a vector for the SARS-CoV structural proteins including S, N, matrix (M), and envelope (E), alone or in combination. Studies with vectored vaccines further demonstrate that induction of S protein specific NAbs is enough to confer protection.

The way this works is, for example, when vaccine developers use genetic engineering to disguise these viruses as SARS-CoV-2 viruses by giving them a corresponding surface protein. This is a particularly good approach when seeking to combat new types of pathogen. When a person is given the vaccine, their body builds up immunity. This protection then enables it to ward off actual infection by the disease. A vector vaccine of this kind was used against smallpox, and the first approved Ebola vaccine is also based on a vector virus. {Johnson and Johnson adeno Virus 26; Serum Institute + OXFORD (Chimp Adeno Virus) Astra Zeneca:

Adjuvants are substances added to vaccines to enhance its immunogenicity. Highly purified antigens that have insufficient immunostimulatory capabilities have been used in human vaccines for more than 90 years. [ Aurbindo CSIR Spike protein; -CHO based, Adjuvanted protein subunit (RBD) Biological]

VLP: Platform Virus Like Particles: Nova vax, Cadila, CLP Biological, supported by BARDA, Australia & US having phase 1, [Rabies, H1N1 trivalent influenza, Now quadrivalent influenza vaccine is being prepared. The same platform has been used by papilloma Merck and GSK. Recently Chikungunya vaccine using the same platform has been developed.

Combination Vaccines against Coronavirus

Combination vaccines have been evaluated for their ability to augment immune responses to SARS-CoV. Administration of two doses of a DNA vaccine encoding the S protein, followed by immunization with inactivated whole virus, was shown to be more immunogenic in mice than either vaccine type alone. The combination vaccine induced both high humoral and cell-mediated immune responses. High NAb titers were also observed in mice vaccinated with a combination of S DNA vaccines and S peptide generated in Escherichia coli. Combination vaccines may enhance the efficacy of DNA vaccine candidates.

The SARS-CoV vaccine strategies reported to date demonstrate that S protein-specific NAbs alone are sufficient to provide protection against viral challenge. While SARS-CoV has not yet reemerged, its unknown reservoir leaves open the possibility that it, or a related virus, will again infect the human population. The development of vaccines targeting this virus will help, in the event of its reemergence, to potentially stop its spread before it wreaks the social and economic havoc caused by the previous outbreak. Furthermore, lessons learned from the generation of these vaccines may aid in the development of future vaccines against known and newly identified coronaviruses.

Disease Modifying:  Immunoglobulins and monoclonal antibodies

Monoclonal Antibodies: directed against infectious pathogens, Most mAbs target proteins on the surface of a virus, thus neutralizing the virus from entering cells. Palivizumab is an antibody against the respiratory syncytial virus (RSV) fusion (F) glycoprotein; it inhibits viral entry into host cells. This is approved by US FDA for the prevention of RSV infection. ('Immunoprophylaxis'.)

Other investigational preventive antiviral mAbs include those targeting the conserved hemagglutinin A stem of Haemophilus influenzae. This therapy may be helpful in cases in which vaccination offers ineffective humoral immunity.

Investigational mAbs against HIV can improve immunity during active infection, with promising results in animal models using broadly neutralizing antibodies

Some mAbs against bacteria can function both prophylactically and therapeutically (eg, by targeting the protective antigen domain of Bacillus anthracis or one of the Clostridioides [formerly Clostridium] difficile toxins).

As stated in 2018, mAbs directed against pathogens are unlikely to be used routinely due to their high cost and requirement for parenteral administration; however, they may be especially useful for certain emerging infectious diseases.

Treatment of active disease and/or targeted prophylaxis might be especially important in individuals who have not been vaccinated against a pathogen but require immediate protection (individuals infected with Ebola virus, pregnant women residing in Zika virus-endemic areas and COVID 19).

1.     Bharat Biotech + NIV + ICMR: Inactivated rabies vector platform
2.     Auro Vaccines Aurbindo Pharma: VesiculoVax platform; Ebola Chickengunya; -CHO conjugate vaccine, adjuvant, spike protein
3.     Gennova Biopharmaceuticals (Messenger RNA vaccine)
4.     Zydus Cadila: DNA Vaccine, Measles vaccine
5.     Emcure GENNOVA mRNA platform
6.     OXFORD: ChAdOx1 nCoV-19, weakened version of chimpanzee adenovirus as vector, infused with the genetic material of spike protein. Also worked on MERS, SARS; Phase-1 clinical trials done 18 to 55 years, across five trial centres in Southern England; The Serum Institute of India will manufacture the vaccine.
7.     Moderna: injects the specially designed messenger RNA (1273 genetic material) produces viral protein or antigen. Mice, ADR monkeys, pre clinical work shows no toxicology at 25/50/250 mcg dose,  Reactogenesis, transient swelling, pain. 28 days dosing space; Phase-1 trails ( 18-55). USFDA nod to begin phase-2. Phase-3. Easy to manufacture, but could be expensive and controlled by USA and BARD
8.     Chinese Sinovac Biotech vaccine: doing phase-1 and phase-2 trials of its COVID-19 vaccine. Previously developing a vaccine against SARS
9.     Pfizer vaccine: with German partner BioNTech are working on four vaccine candidates, each representing a different combination of messenger RNA method and target antigen.
10.  VC Hope Clinic Responds to COVID-19: Recruitments of volunteers, USA each strata, India poor people, need all strata
11.  The Emory Vaccine Center's Hope Clinic is at the forefront of the COVID-19 response. The Emory Hope Clinic is working hard in the fight against COVID-19 through clinical vaccine and treatment trials, virtual community outreach, and in-office protective measures. If you qualify for a clinical trial or study please contact the Emory Hope Clinic at: 404.712.1370.
12.  Novavax: NVX-CoV2373, Phase 1 clinical trial, preclinical studies, high immunogenicity, high levels of neutralizing antibodies, First-in-human Phase 1 clinical trial accelerated to mid-May with preliminary results in July, GMP clinical production initiated at Emergent BioSolutions with ability to leverage capacity for large scale manufacturing, VLP platform, Cadila pharma, CLP biological, BARDA, USA Australia, Phase 1],
13.  Johnson and Johnason: Adeno 26, non oncho, spike, RSV phase 3, ebola,
14.  Zydus, measles virus platform
15.  Disease modifying vaccines, mab, immunoglobulins,

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