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(With inputs from Dr N K Ganguly, Dr Rajan Sharma, Dr RV Asokan)
841: Coronavirus vaccines
- Coronaviruses: Virus Spike protein, Envelope, Membrane, RNA, Nucleic
- Difficulties: Virus behaves like HIV, causes immune inflammation, causes cytokine storm, causes thrombo-inflammatory reactions, brings down immunity and has latency
- Immunity: Short-term or long-term; Booster doses, immunity lasting one year
- Herd Immunity Threshold: R-1/R, Protecting older people, Disabled people, immunocompromised people.
- Development Time long: 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
- Because people have no immunity to COVID-19, its 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.
- There are 120 vaccine initiatives 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 initiated the testing of an inactivated version of SARS-CoV-2 in humans. The inactivated version will also be developed in the Serum Institute.
- Viral-vector vaccines (Replicating or non-replicating): The following platforms are being used: Measles, Chimp adenovirus, Adenovirus 26, Pox virus vectors, etc.
- 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 churns out copies of the virus protein; most of these vaccines encode the virus’s spike protein.
- 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).
Live attenuated: Radiation, heat, chemicals; harmless virus; MMR, smallpox and chickenpox; weak immunity
To date, live attenuated vaccines for COVID-19 virus have not been assessed. Systems have been developed to prepare cDNAs encoding the genomes of CoVs, including SARS-CoV. It is possible to systematically and directionally assemble the panel of cDNAs spanning the entire CoV genome 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 help in engineering 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, it has been observed that infectious virus is shed in the feces of SARS-CoV-infected individuals. This raises concerns that a live attenuated SARS-CoV vaccine strain may also be shed in feces, which can potentially spread to unvaccinated individuals. There is yet another concern - 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 shown in experimental animals. One such vaccine is currently under evaluation in a clinical trial. The development of inactivated vaccines is associated with the propagation of high titers of infectious virus. In the case of SARS-CoV, this requires biosafety level 3-enhanced precautions and is a safety concern for production. Incomplete inactivation of the vaccine virus is also a potential public health threat. Production workers face a risk for infection during handling of concentrated live SARS-CoV. Furthermore, incomplete virus inactivation can potentially lead to SARS outbreaks among the vaccinated populations, and some viral proteins may induce harmful immune or inflammatory responses, resulting in SARS-like diseases.
Genetically engineered: RNA or DNA carrying instructions for making copies of the S protein is used. These copies prompt an immune response to the virus. No infectious virus needs to be handled with this approach. None of the genetically engineered vaccines has been licensed for human use.
DNA vaccines induce immune responses to viral pathogens in animal models, specifically in mice. Clinical data in human subjects are; however, limited. DNA vaccines encoding the S, N, M, and E proteins of SARS-CoV have been studied in mice. Vaccination with S-, M-, and N-encoding DNA vaccines have been shown to induce both humoral and cellular immune responses, with some variation in the relative levels of induction.
S protein’s role in receptor binding and membrane fusion suggests that vaccines based on the S protein could induce antibodies that inhibit virus binding and fusion or neutralize virus infection. Of all the structural proteins of SARS-CoV, S protein is the key antigenic component that induces host immune responses, neutralizing antibodies and/or protective immunity against virus infection. S protein is an important target for vaccine and anti-viral development.
While full-length S protein-based SARS vaccines can induce neutralizing antibody responses against SARS-CoV infection, they also have the potential to induce harmful immune responses against host or enhanced infection after challenge with homologous SARS-CoV, thus raising concerns about the safety and protective efficacy of vaccines containing the full-length SARS-CoV S protein.
The gene-based vaccines: Carry pure genetic information as coronavirus DNA or mRNA. Individual components of this genetic information from the pathogen are packed into nanoparticles and then introduced into cells. As the vaccine enters the body, it should form harmless viral proteins that boost immune protection. These vaccines are in in the pipeline. The first vaccine to have completed Phase I is 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) is a live attenuated parainfluenza virus vaccine candidate that has been used as a vector for the SARS-CoV structural proteins including S, N, matrix (M), and envelope (E), either alone or in combination. Studies conducted with vectored vaccines have shown that induction of S protein specific NAbs is enough to confer protection.
How does this work? Vaccine developers use genetic engineering to disguise these viruses as SARS-CoV-2 viruses by giving them a corresponding surface protein. This is a promising approach when fighting new types of pathogens. As a person receives the vaccine, his body builds up immunity. This protection enables it to fight actual infection by the disease. Such a vector vaccine 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 Adenovirus)]
Adjuvants are added to vaccines to enhance their immunogenicity. Highly purified antigens with insufficient immunostimulatory capabilities have been used in human vaccines for over 90 years. [Aurobindo CSIR Spike protein; -CHO based, Adjuvanted protein subunit (RBD) Biological]
VLP: Platform Virus Like Particles: Novavax, Cadila, CPL Biologicals, 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 Merck and GSK. Recently Chikungunya vaccine using the same platform has been developed.
Combination Vaccines against Coronavirus
Combination vaccines have been assessed for their potential to enhance immune responses to SARS-CoV. Administration of two doses of a DNA vaccine encoding the S protein, followed by inactivated whole virus vaccine has been found to be more immunogenic in mice compared to either vaccine type alone. The combination vaccine was shown to induce both high humoral and cell-mediated immune responses. High NAb titers have also been noted in mice vaccinated with a combination of S DNA vaccines and S peptide generated in Escherichia coli. Combination vaccines tend to augment the efficacy of DNA vaccine candidates.
The SARS-CoV vaccine strategies reported till today have shown that S protein-specific NAbs alone can provide protection against viral challenge. Although SARS-CoV has not reemerged as yet, its unknown reservoir still makes it possible that it, or a related virus, can again infect humans. The development of vaccines targeting this virus will help if the virus re-emerges, to potentially curb its spread before it wreaks social and economic havoc. Lessons learned from the generation of these vaccines may help generate 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, and neutralize the virus from entering cells. Palivizumab, an antibody against the respiratory syncytial virus (RSV) fusion (F) glycoprotein, 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 the ones that target the conserved hemagglutinin A stem of Haemophilus influenzae. This may help in cases in which vaccination offers ineffective humoral immunity.
Investigational mAbs against HIV have the potential to improve immunity during active infection. The results have been promising in animal models using broadly neutralizing antibodies.
Some mAbs against bacteria can act both prophylactically and therapeutically (for instance, by targeting the protective antigen domain of Bacillus anthracis or one of the Clostridioides difficile toxins).
As stated in 2018, mAbs directed against pathogens are unlikely to be used routinely owing to high cost and requirement for parenteral administration. They may be particularly useful for certain emerging infectious diseases.
Treatment of active disease and/or targeted prophylaxis might be important in those who have not been vaccinated against a pathogen but require immediate protection (such as those infected with Ebola virus, pregnant women residing in Zika virus-endemic areas and COVID-19).
- Bharat Biotech + NIV + ICMR: Inactivated rabies vector platform
- Auro Vaccines Aurobindo Pharma: VesiculoVax platform; Ebola Chikungunya; -CHO conjugate vaccine, adjuvant, spike protein
- Gennova Biopharmaceuticals (Messenger RNA vaccine)
- Zydus Cadila: DNA Vaccine, Measles vaccine
- Emcure GENNOVA mRNA platform
- 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 centers in Southern England; The Serum Institute of India will manufacture the vaccine.
- 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 trials ( 18-55). USFDA nod to begin phase-2, Phase-3. Easy to manufacture, but could be expensive and controlled by USA and BARDA
- Chinese Sinovac Biotech vaccine: doing phase-1 and phase-2 trials of its COVID-19 vaccine. Previously developing a vaccine against SARS
- Pfizer vaccine: with German partner BioNTech, are working on four vaccine candidates, each representing a different combination of messenger RNA method and target antigen.
- VC Hope Clinic Responds to COVID-19: Recruitments of volunteers, USA each strata; India poor people, need all strata
- The Emory Vaccine Centers Hope Clinic is at the forefront of the COVID-19 response. The Emory Hope Clinic is working on clinical vaccine and treatment trials, virtual community outreach, and in-office protective measures.
- Novavax: NVX-CoV2373, Phase 1 clinical trial, pre-clinical 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, CPL biological, BARDA, USA, Australia, Phase 1]
- Johnson and Johnson: Adeno 26, non oncho, spike, RSV phase 3, Ebola
- Zydus: measles virus platform
- Disease modifying vaccines, mAb, immunoglobulins
Dr KK Aggarwal
President CMAAO, HCFI, Past National President IMA, Chief Editor Medtalks