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Future unclear for Italy’s COVID-19 vaccine

Leggi in italiano

A researcher at work in the ReTthera laboratories in Castel Romano, near Rome. Credit: Alessandro Serrano/AGF/Universal Images Group via Getty Images.

As researchers and drug developers around the world scrambled to develop and produce vaccines to stop the spread of COVID-19, a small biotech company outside Rome called ReiThera joined the race. In August 2020, with financial backing from the Italian government, it started an early-stage trial of its COVID-19 candidate vaccine. The company hoped to produce up to 100 million doses per year.

Touted as an opportunity to make Italy self-sufficient in COVID-19 vaccine production, ReiThera’s candidate has faced a series of setbacks, including a court’s ruling against a €50-million public investment into the firm. On 12 July, the company announced that its vaccine candidate elicited a strong immune response and no major side effects in intermediate clinical trials.

ReiThera’s vaccine is based on a gorilla-derived adenovirus, engineered so that it can’t replicate in human cells. The adenovirus carries genetic instructions for the spike protein that SARS-CoV-2 uses to infect host cells. The vaccine causes the spike protein to be expressed by the cells of vaccinated people, triggering an immune response. A similar approach is used by US-based pharma company, Johnson & Johnson, and British-Swedish biotech firm AstraZeneca.

In July 2020, the Italian drug regulator authorized a small phase-1 trial of ReiThera’s vaccine. The trial, supported by €8 million in public funding, involved 90 volunteers aged 18-85 and showed that, within four weeks after the jab, more than 97% of people produced ‘neutralizing’ antibodies — immune molecules that can block infection — and T cells that activate other immune responses. Volunteers only experienced mild side effects such as headaches, fatigue and pain at the site of injection.

The findings, posted in April on the preprint server medRxiv, have not yet been peer reviewed. Three researchers who were not involved in the study told Nature Italy that the results suggest the vaccine is safe and can induce an immune response that is consistent with that observed with other types of adenovirus-based vaccines. “It’s a good study,” said Akiko Iwasaki, an immunologist at Yale University in New Haven, Connecticut, who studies immune responses to SARS-CoV-2.

In March, ReiThera started a phase 2 clinical trial, which was run by 25 research groups across Italy and involved more than 900 volunteers. According to the statement released by the company on 12 July, the preliminary findings from the study largely confirm the results of phase 1. The vaccine induced an antibody response in more than 93% of volunteers three weeks after the first dose, reaching 99% after the second dose. No serious side effects were reported, the company said.

The results are “definitely encouraging”, says Antonio Cascio, director of the unit for tropical and infectious diseases at Policlinico Paolo Giaccone in Palermo, who leads one of the research groups that ran the trial.

Enrico Bucci, a molecular biologist who leads a science-integrity company in Samone, says he would like to see detailed data on the age of the trial participants and the levels of neutralizing antibodies elicited before drawing conclusions on the vaccine’s efficacy. In the phase 1 preprint, he notes, the levels of neutralizing antibodies were comparable to those of people who had mild COVID-19, but lower than those of individuals who had severe disease. Because the higher the levels of neutralizing antibody that someone produces, the more likely they are to be protected, Bucci said it’s unclear how effective the vaccine is.

In an email to Nature Italy, ReiThera wrote that 19% of the phase 2 trial participants were above 65 years of age, and that the level of antibodies induced by their vaccine is comparable to that of a reference group including both hospitalized and mild cases, similarly to what was reported for the vaccines already approved. The company also wrote that it expects to release a preprint with the consolidated data between September and October.

ReiThera said that two independent advisory boards have recommended advancing the vaccines into late-stage, phase 3 trials, which would involve thousands of volunteers. But at the moment it is unclear how that trial can be funded.

In May, during the phase 2 study, Italy’s court of audit — which oversees public spending — rejected an earlier agreement between Italy’s Ministry for Economic Development (MISE), the state-owned investment agency Invitalia, and ReiThera, under which the company was to receive €49 million to fund late-stage clinical trials and expand its vaccine production facility. The court was dissatisfied with the fact that the investment wasn’t limited to the activities strictly related to the development of the vaccine, but also included the purchase of the firm’s headquarters.

After the ruling, MISE said that it was open to contribute to ReiThera’s vaccine project, but no solution has been announced so far. Some funds might come from Enea Tech e Biomedical, a new foundation created by MISE to invest in start-ups and emerging technologies, with a €900 million budget.

“At the moment, we have no information on phase 3 [trials],” says Sergio Lo Caputo, director of the infectious diseases unit at Policlinico Riuniti in Foggia, whose team was among those that conducted the phase 2 study.

Discussions between ReiThera and Italian institutions are ongoing, the company wrote in its email. MISE has not responded to request for comment from Nature Italy.

If ReiThera does manage to secure funding, running late-stage trials may prove challenging. The company announced that it will compare its vaccine with one of the adenovirus vaccines that have already been approved. Because the number of COVID-19 cases is falling in countries with access to effective vaccines, ReiThera’s phase 3 trial may take longer or require a larger number of participants.

One option would be to run the studies in countries where the circulation of the virus is high and immunization coverage is still low, says Stefano Milleri, scientific medical director of the Centro Ricerche Cliniche in Verona, which conducted both phase 1 and phase 2 trials of ReiThera’s vaccine candidate. Reithera wrote to Nature Italy that it will run a feasibility study in order to choose the most suitable countries for the phase 3 study, and that it’s had preliminary contacts with non-European countries that could be interested.

If approved, the vaccine may arrive on the market after most of the population is already vaccinated, at least in many countries. The company wrote to Nature Italy that “it would make sense” to use it for booster shots, to maintain efficacy against new variants. But a number of countries have paused or restricted the rollout of two vaccines based on adenoviral vectors (AstraZeneca’s and Johnson & Johnson’s) citing concerns that they may be linked to rare blood clots in a small number of recipients. With many people already hesitant to take a COVID-19 vaccine, it may be difficult to persuade them to get an adenovirus jab, says Antonella Viola, an immunologist at Università di Padova. The use of the adenovirus technology for booster shots to fight new variants would be anyway problematic, she suggests. After getting an adenovirus-based COVID-19 vaccine, people develop immune responses not only against SARS-CoV-2’s spike protein, but against the adenoviral vector itself, making it less effective upon repeated injections.

Former director of the Italian Medicines Agency Luca Pani says that ReiThera’s vaccine would have to compete with technologies such as mRNA vaccines, that don’t use another virus as a vector and allow for quick updates as new variants emerge. But mRNA vaccines are more expensive and less stable at room temperature, making distribution and storage difficult. ReiThera’s vaccine could help to ramp up immunizations in low- and middle-income countries, Pani says.

doi: https://doi.org/10.1038/d43978-021-00089-4

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