While all COVID-19 vaccines administered through the intramuscular route have been found to reduce the chances of symptomatic disease and death, attempts are being made to develop vaccines that can potentially prevent or at least greatly reduce the chances of being infected and also stop the spread of the virus. Such vaccines are typically administered at the site of infection, and the most efforts are at developing vaccines that can be administered intranasally either as drops or as a spray.

Developed by Washington University School of Medicine in St. Louis, the vaccine has been licensed to Bharat Biotech to carry out human clinical trials, manufacture the vaccine and distribute them in all countries except the U.S., Japan and Europe. Bharat Biotech has already begun the phase-1 clinical trials at four sites in India – Hyderabad, Nagpur, Patna and Chennai.

Clinical trial

According to details posted on the U.S. clinical trial registry, the vaccine will be tested on 175 participants as single and double doses in the phase-1 trial. There will be three arms – single dose, double dose and placebo. There will be 70 participants each who will get a single dose and double dose (day 0 and 28), and the placebo arm will have 35 participants.

Much like the Oxford vaccine, the intranasal vaccine has been developed using the vector-based platform and uses a chimpanzee adenovirus (Ad 36) to ferry the spike protein of SARS-CoV-2 virus.

A single dose of the intranasal vaccine has been found to induce robust mucosal immunity, which prevents SARS-CoV-2 infection in the upper and lower respiratory tracts of mice when challenged with the virus a few weeks after vaccination. Robust humoral and cell-mediated immune responses were also seen. In the case of hamsters, a single dose of the vaccine provided “superior protection” of the nasal cavity and upper respiratory tract, which may confer protection against both infection and transmission. Even in the case of rhesus monkeys, a single intranasal dose of the vaccine induced neutralising antibodies and T cell responses and was found to limit or prevent infection in the upper and lower respiratory tract once challenged with the virus.

Even if the vaccine is unlikely to confer sterilising immunity, the local mucosal immunity is likely to reduce the possibility of infection and in all probability might prevent transmission. “Whether it confers sterilising immunity or not will become clear only during human trials. But it is more likely to reduce infection though the extent of reduction remains to be seen,” says immunologist Dr. Satyajit Rath, formerly with the National Institute of Immunology, Delhi and now a visiting faculty at IISER Pune.

“The intranasal vaccine is very unlikely to confer sterilising immunity. So far, only the HPV vaccine has been found to confer sterilising immunity,” says virologist Dr. Jacob John, formerly with CMC Vellore. “The vaccine may also not prevent infection but can surely reduce the speed of transmission.”

Duration of protection

While Dr. Rath is unsure how long the duration of protection conferred by local mucosal immunity might last and thinks that it might be the same as when the vaccine is administered through intramuscular route, Dr. John says the local mucosal immunity will be short-lived, perhaps for months to a year.

Dr. John also points out that for diseases where transmission is either by respiratory or faecal-oral route, vaccines administered through the intramuscular route have been equally effective in either preventing infection or disease onset. In contrast, the oral polio vaccine has to be administered repeatedly to confer continued protection.

A typical example is HPV, where sterilising immunity at the site of infection is achieved even though it is an intramuscular vaccine. “Even if one cell is infected, the process of chronic infection and malignancy continue. This is the only vaccine that prevents even one cell from getting infected, and it is due to sterilising immunity,” says Dr. John.

Case of measles

In the case of measles, which is highly contagious, a vaccinated child can get infected but may not suffer from disease. “Measles spreads only after disease sets in. Since the vaccinated child does not suffer from disease the child does not spread the virus through the nasal route,” he explains.

In the case of whooping cough, it’s the toxin and not the bacteria per se that causes disease. A child can get infected despite being vaccinated intramuscularly, but the vaccine-induced immunity reduces the chances of disease even when infected, says Dr. John.

In the case of diphtheria, where the infection will be sub-clinical, for the disease to get worse large-scale multiplication of the bacteria on the mucosal surface is needed, which is facilitated by the toxin. When the toxin is not effective due to the presence of toxin antibodies, the growth of the bacteria is compromised and disease onset is prevented.

The biggest advantage that intranasal vaccine offers is the ease of vaccine administration, particularly when the vaccine is administered as drops. There will be no need for trained health workers for intramuscular administration. Just like in the case of oral polio vaccination, the use of a cheap dropper to administer the vaccine to multiple people will make the vaccination drive easy, simple and cost-effective.

If any intranasal vaccine is found to be safe and highly efficacious even against variants, and if the vaccine is available in large quantities, the possibility of administering the vaccine to large populations within a short time to check the spread of the virus may be possible. Dr. John is even optimistic of eradicating the virus if the world comes together to administer an efficacious intranasal vaccine within a short time frame. “It all boils down to a design issue for eradication,” he says.