New Temperature Sensitive Poliovirus Strains Show Potential for Use in ‘Next-gen’ Vaccines

The three strains are adapted to cold temperatures but can multiply at up to 30 ºC, an international team of scientists from Europe has reported.

An electron micrograph of a representative cell 24-48 hours after being infected with CAVA strains. Source:

An electron micrograph of a representative cell 24-48 hours after being infected with CAVA strains. Source:

Scientists have found three novel poliovirus strains that can’t replicate at room temperature (37 ºC), thanks to multiple irreversible mutations. Such a feature bestows on them an enormous potential for use in making new-generation vaccines. The three strains are adapted to cold temperatures but can multiply at up to 30 ºC, an international team of scientists from Europe reported in the journal PLoS Pathogens on March 31This inability to multiply at room temperature “would impede reversion to neurovirulent form”, resulting in a non-pathogenic version in the natural host, according to their paper.

They identified 14 mutations whose combination could induce the temperature sensitivity. Tests in rats showed that the strains helped the rodents produce antibodies against the polio virus. The three new strains, which the scientists call cold adapted viral attenuation (CAVA) vaccine strains, “could contribute to genetically stable, efficacious and affordable” inactivated polio vaccines (IPV).

Currently, there are two types of polio vaccines that have formed the backbone of the global polio eradication programme. One is the conventional inactivated polio vaccine cIPV, developed by Jonas Salk in 1955. It contains three inactivated, wild-type virulent poliovirus strains. The second is the oral polio vaccine (OPV) developed in the 1960s by Albert Sabin, which contains three live but weakened, or attenuated, poliovirus strains. Globally, the world is moving toward the withdrawal of OPV and implementation of cIPV – as well as the replacement of virulent polio virus strains used in cIPV with attenuated strains.

India includes a dose, or two fractional doses given through the skin, of inactivated polio vaccine in the national program following the guidelines of the Global Polio Eradication Initiative and the World Health Organisation (WHO). In April 2016, it will switch from using the trivalent OPV to the bivalent vaccine, which does not include poliovirus type 2.

In the past, cold-adaptation has been used to find attenuated viruses for the purpose of making a vaccine, Barbara Sanders, one of the lead authors of the report and a scientist at the pharmaceutical division, Johnson and Johnson, the Netherlands, explained to The WireHowever, this is the first time that such a definitive block in replication has been observed at 37 ºC, she said. Other cold-adapted polioviruses identified earlier could still replicate but only at lower rates at the same temperature.

“The extent of temperature sensitivity observed for these strains has never been described before,” she added. The viruses were not obtained directly from any infected persons but are a synthetic combination of cold-adaptation mutations as well as some proteins from the outer shell of the virus, from existing vaccine strains, which are necessary to make candidate vaccine strains. The three novel strains are at an early stage of discovery, and more work will be needed before they will qualify for use in vaccines, says Sanders. The immediate next step will be to conduct more pre-clinical tests and further elucidate the molecular mechanism of temperature sensitivity and attenuation.

“Upon completion of such pre-clinical work, a suitable manufacturing process would need to be defined and clinical testing to be performed to assess the safety of a potential CAVA based vaccine and ultimately the effectiveness. [That is], does it provide an adequate protective immune response in humans?”

“This paradigm of having a vaccine strain that replicates at low temperatures and is capable of inducing immunity without causing disease because of its inability to replicate in target organs at the body temperature of the host may be useful for future human and animal vaccine development,” says Gagandeep Kang, professor at the division of gastrointestinal sciences at Christian Medical College (CMC), Vellore.

“The current IPV vaccines work very well” and “the search for non-pathogenic strains of polioviruses from which IPV can be made is an insurance policy for the future so that inactivated vaccines have close to zero chance of causing polio,” she says. “Another approach to new IPVs includes the use of attenuated, immunogenic strains that are in the current oral poliovirus vaccine as live strains.”

T. Jacob John, India’s renowned vaccine expert and emeritus professor at CMC, says the usefulness of cold-adapted polioviruses is for manufacturing IPV, the only acceptable vaccine going ahead. Currently, wild polioviruses, maintained in lab stocks, are the base or raw material from which IPV is made and they require elaborate containment systems that conform to the highest biosafety level, BSL 4.

Despite having argued in favour of IPVs in the past, John had few takers for his opinion at the time.”The world’s experts did not accept my scientific arguments about why IPV is essential to complete and conclude global polio eradication, until 2012. In 2016, we are removing type 2 Sabin virus from OPV. By end of 2016, all countries must use IPV. The delay in the acceptance by experts meant delay in giving green signal to scientists as well as IPV manufacturers for improving [its] production,” he says.  

If Sabin viruses are used instead, the containment is less sensitive because the consequence of any leak is less formidable than that of wild viruses, he says. Japan uses exclusively Sabin IPV; China is ready with its version Sabin IPV for its own needs. India’s public sector vaccine-making units were “never keen to manufacture IPV, or to allow it in private sector by some logic of the Ministry of Health and Family Welfare,” John adds. “In the private sector, there seems to be some interest in Sabin viruses as the first choice. This cold-adapted virus offer another safer route, but further validation will take time and money.”