(With inputs from Dr Monica Vasudeva)

808: Coronavirus vaccine research

Coronaviruses possess a spike-like structure on their surface known as S protein. These spikes create the corona-like, or crown-like, appearance, thus giving the viruses their name. The S protein attaches to the surface of human cells. A vaccine targeting this protein would prevent it from binding to human cells and thus intercept the reproduction of the virus.

809: Coronavirus vaccine challenges

Past research on vaccines for coronaviruses has identified some challenges to developing a COVID-19 vaccine. These include:

Ensuring vaccine safety: Several vaccines for SARS have been tested in animals. Most of the vaccines were shown to improve survival but didnt prevent infection. Some vaccines also led to complications, such as lung damage. A COVID-19 vaccine thus needs to be thoroughly tested to ensure that its safe for humans.

Providing long-term protection: Following infection with coronaviruses, re-infection with the same virus, although often mild and happening only in a fraction of people, is possible after months or years. An effective COVID-19 vaccine will be one that would provide long-term infection protection.

Protecting older people: People over 50 have a greater risk of severe COVID-19 infection. Older individuals; however, dont respond to vaccines as well as younger people. Therefore, an ideal COVID-19 vaccine would work well for this age group.

Pathways to develop and produce a COVID-19 vaccine

810:  Live vaccines

Live vaccines employ an attenuated form of the germ known to cause the disease. Such a vaccine prompts an immune response without causing disease. The vaccines ability to cause disease has been reduced in an attenuated form.

The starting point for a live vaccine is a virus that is known, but harmless. It does not cause disease, but is able to multiply within the cells of our bodies. This is the vector which then triggers an immune response.

Live vaccines are used to protect against measles, mumps, rubella, smallpox and chickenpox. The infrastructure is in place to develop such vaccines. However, live virus vaccines need extensive safety testing. Some live viruses can be transmitted to a person who isnt immunized. This is particularly concerning for people with weakened immune systems.

811: Inactivated vaccines

Inactivated vaccines use a killed, or an inactive, form of the germ that causes a disease. Such vaccines incite an immune response but not infection. Inactivated vaccines are often used to prevent flu, polio, hepatitis A, B, tetanus, whooping cough and rabies.

The dead viruses do not multiply, but the body still recognizes them as intruders. The bodys defense system produces antibodies and the vaccinated individual does not develop the disease.

Inactivated vaccines may not provide as strong a protection as that produced by live vaccines. This type of vaccine often requires multiple doses, followed by booster doses, to provide long-term immunity. Preparing these vaccines might require the handling of large amounts of the infectious virus.

812: Genetically engineered vaccines

These vaccines use genetically engineered RNA or DNA that has instructions for making copies of the S protein. These copies incite an immune response to the virus. No infectious virus needs to be handled with such an approach. Genetically engineered vaccines are currently in the works, but none has been licensed for human use yet.

813: The vaccine development timeline

The development of vaccines can take years, more so, when the vaccines involve new technologies that havent been tested for safety or adapted to allow for mass production.

814: Why does it take so long?

A vaccine is first tested in animals to see if it works and if its safe. This testing is conducted under strict lab guidelines and usually takes three to six months. Manufacturing of vaccines also must follow quality and safety practices.

The vaccine is then tested in humans. Small phase I clinical trials are conducted to evaluate the safety of the vaccine in humans. During phase II, the formulation and doses of the vaccine are established to prove its effectiveness. Phase III ascertains the safety and efficacy of a vaccine in a larger group of people.

Its unlikely that a COVID-19 vaccine will become available sooner than six months after clinical trials start. A vaccine takes 12 to 18 months or longer to develop and test in human clinical trials. And it is not known yet whether an effective vaccine is possible for this virus.

If a vaccine is approved, it will take time to produce, distribute and administer to the global population. People have no immunity to COVID-19, therefore, two vaccinations will likely be required, three to four weeks apart. People would likely start achieving immunity to COVID-19 one to two weeks after the second vaccination.

815: Monoclonal Antibodies (808)

The use of mAbs directed against infectious pathogens is an area of investigation. The mechanism is not completely understood. Potential uses include prevention or treatment of specific infections.

Most mAbs target proteins on the surface of a virus and neutralize 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. The therapy got US FDA approval for the prevention of RSV infection. (Immunoprophylaxis)

Other investigational preventive antiviral mAbs include those that target the conserved hemagglutinin A stem of Haemophilus influenzae. This therapy may help 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, for instance, by targeting the protective antigen domain of Bacillus anthracis or one of the Clostridioides [formerly Clostridium] difficile toxins.

A 2018 editorial stated that mAbs directed against pathogens are unlikely to be used routinely owing 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 (those infected with Ebola virus, pregnant women residing in Zika virus-endemic areas and COVID 19). [Uptodate]

816: Inactivated Coronavirus Vaccine

The immunogenicity and efficacy of inactivated SARS-CoV vaccines have been demonstrated in experimental animals, and one such vaccine is under evaluation in a clinical trial. However, the development of inactivated vaccines calls for 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 poses a potential public health threat. Production workers are also at risk for infection during handling of concentrated live SARS-CoV. Incomplete inactivation of the virus can lead to SARS outbreaks among the vaccinated populations, and some viral proteins may induce harmful immune or inflammatory responses, and may even cause SARS-like diseases.

817: Live Attenuated Coronavirus Vaccine

Live attenuated vaccines for SARS-CoV have not yet been evaluated. Systems are in place 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 helps with the genetic analysis of SARS-CoV protein functions and will allow researchers to engineer specific attenuating mutations or modifications into the genome of the virus to develop live attenuated vaccines. Live attenuated vaccines that target respiratory viruses, including influenza viruses and adenoviruses, have been approved for human use; however, 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, with potential to spread to unvaccinated individuals. There is another concern associated with this. There 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.

818: S Protein-based Coronavirus Vaccine

The roles of S protein in receptor binding and membrane fusion have suggested that vaccines based on the S protein could induce antibodies to block virus binding and fusion or neutralize virus infection. Of all the structural proteins of SARS-CoV, S protein is the key antigenic component known to induce host immune responses, neutralizing antibodies and/or protective immunity against virus infection. S protein is therefore an important target for vaccine and anti-viral development.

Full-length S protein-based SARS vaccines can induce neutralizing antibody responses against SARS-CoV infection. Yet, they may also induce harmful immune responses causing liver damage of the vaccinated animals or enhanced infection after challenge with homologous SARS-CoV. This raises concerns about the safety and the protective efficacy of vaccines that contain full-length SARS-CoV S protein.

819: Vectored Vaccines against Coronavirus

Preclinical evaluation of vaccines has been reported using other viruses as vectors for SARS-CoV proteins, including a chimeric parainfluenza virus, MVA, rabies virus, vesicular stomatitis virus (VSV), and adenovirus. Chimeric bovine/human parainfluenza virus 3 (BHPIV3), a live attenuated parainfluenza virus vaccine candidate, has been utilized as a vector for the SARS-CoV structural proteins including S, N, matrix (M), and envelope (E), alone or in combination. Investigations with vectored vaccines further show that induction of S protein-specific NAbs is sufficient to confer protection.

How does this work? - 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 looking to fight new types of pathogen.

When a person receives the vaccine, the body builds up immunity. This protection then 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 a vector virus vaccine.

820: DNA Vaccines against Coronavirus

DNA vaccines have shown strong induction of immune responses to viral pathogens in animal models, particularly in mice. Clinical data on DNA vaccines in human subjects are scarce. 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 was noted to induce humoral as well as cellular immune responses, with some variation in the relative levels of induction.

821: Combination Vaccines against Coronavirus

Combination vaccines have been evaluated for their ability to enhance immune responses to SARS-CoV. Two doses of a DNA vaccine encoding the S protein, followed by immunization with inactivated whole virus, have been noted 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 have also been observed 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 till today show 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 humans. If it reemerges, the development of vaccines targeting this virus will help stop its spread before it wreaks the social and economic havoc caused by the previous outbreak. Lessons learned from the generation of these vaccines may also help in the development of future vaccines against known and newly identified coronaviruses.

822: The gene-based vaccines

These contain pure genetic information in the form of coronavirus DNA or mRNA. Individual parts of genetic information obtained from the pathogen are packed into nanoparticles and are introduced into cells. As the vaccine enters the body, it should form harmless viral proteins that build up immune protection. No such vaccine exists on the market thus far. They are still in the development phase, with various companies and institutes conducting research. The first vaccine to receive Phase I approval in Germany is an mRNA vaccine.

Summary

1. Virus vaccines (Live attenuated or inactivated):At least seven teams are developing vaccines using the virus itself, in a weakened or inactivated form. Several existing vaccines are made this way, including those against measles and polio, but they require extensive safety testing. Sinovac Biotech in Beijing has initiated testing of an inactivated version of SARS-CoV-2 in humans.
2. Viral-vector vaccines (Replicating or non replicating): Nearly 25 groups are working on viral-vector vaccines. A virus such as measles or adenovirus is subjected to genetic engineering so that it can produce coronavirus proteins in the body. These viruses are weakened and cannot cause disease. There are two types - those that can still replicate within cells and those that cannot as the key genes have been disabled.
3. Nucleic-acid vaccines: Some 20 teams aim to use genetic instructions (in the form of DNA or RNA) for a coronavirus protein that incites 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
4. Protein-based vaccines: Many researchers want to inject coronavirus proteins directly into the body. Fragments of proteins or protein shells that mimic the coronavirus’s outer coat can also be used (virus subunit or virus like particle).

Dr K K Aggarwal,

President CMAAO, HCFI, Past National President IMA, Chief Editor Medtalks