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Dr KK Aggarwal 15 May 2020
(With inputs from Dr N K Ganguly, Dr Rajan Sharma, Dr RV Asokan)
841: Coronavirus vaccines
General
Vaccine Types
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).
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Dr KK Aggarwal
President CMAAO, HCFI, Past National President IMA, Chief Editor Medtalks
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