Medicago, GSK post positive midphase data on plant-derived COVID-19 vaccine

Medicago and GlaxoSmithKline have presented interim phase 2 data on their adjuvanted COVID-19 vaccine candidate. The results suggest the plant-derived jab CoVLP+AS03 is somewhat differentiated from other vaccines through the mixed cellular response it triggers.

The vaccine candidate consists of self-assembling viruslike particles (VLPs) that display trimers of recombinant S protein from SARS-CoV-2. Medicago has paired the VLPs, which it makes in Nicotiana benthamiana, a close relative of tobacco, with GSK’s oil-in-water adjuvant system AS03 to initiate an innate immune response that supports the subsequent adaptive immune response to the vaccine.

In a preprint paper, Medicago shared safety, tolerability and immunogenicity data from hundreds of adults who received two doses of the vaccine three weeks apart. The update offers encouragement that the vaccine is safe, tolerable and triggers an immune response against the coronavirus. 

Neutralizing antibody levels rose somewhat in the 21 days after the first dose, and jumped over the 21 days after the second shot. The Day 42 antibody response was similar in adults aged under and over 65 years. Medicago said the antibody levels were 10 times higher than those seen in patients recovering from COVID-19.

The researchers also shared data on cell-mediated immunity as measured by IFN-γ and IL-4 assays. Medicago saw IFN-γ levels rise a little by Day 21 before taking off in the weeks after the second dose. The pattern was similar in both age groups, but the response was weaker in older adults.

Medicago also saw a notable IL-4 response by Day 42, again with the highest activity being seen in the under-65 cohort. The first wave of COVID-19 vaccines was Th1-biased, leading to a strong IFN-γ response but limited IL-4 activity, but the Medicago candidate is more balanced. 

There is a potential downside to the level of IL-4 response triggered by the Medicago vaccine. In the early days of COVID-19 vaccine development, there were concerns that Th2-type responses, which are characterized by IL-4 production, could cause vaccine-associated enhanced disease (VAED). Data on the Th1-biased vaccines allayed those concerns, but CoVLP+AS03 has a different profile.

The authors of the preprint downplayed the concern, observing that there is no evidence of VAED in animal models and clinical trials nor any evidence that Th2 responses are associated with disease enhancement. Going further, the authors outlined potential benefits to the Th2 response.  

“It [is] even possible that the Th2-response induced by CoVLP+AS03, as characterized by IL-4 production, may contribute significantly to the high titers of neutralizing antibody observed in vaccinated subjects through its role in T helper follicular cell involvement, optimal germinal center formation and B-cell maturation,” the authors wrote. “Such Th2-driven effects may also contribute to longevity of SARS-CoV-2 specific memory B-cell responses and longer-term immune response.”

Medicago has seen no cases of VAED nor any grade 4 or 5 adverse events. Local reactions were common, particularly pain in younger people and following the second dose, but grade 3 events were rare. The data on solicited systemic reactions follow a similar pattern.

A phase 3 trial of CoVLP+AS03 got underway in March. The timeline puts Medicago well behind the leading vaccines, but there is a chance CoVLP+AS03, which can be stored at 2 degrees Celsius and 8 degrees Celsius, can still play a role in the global immunization effort. Medicago and GSK released the data shortly after Sanofi shared phase 2 results on its AS03-adjuvanted COVID-19 vaccine.