Pneumonia Vaccine at Higher Dose Boosts Immunity With Rituximab

Phase 2 trial in AAV patients compared standard to reinforced vaccinations

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A reinforced pneumonia (pneumococcal) vaccination scheme, where one of the two vaccine types available is given at higher doses than usual, appears to be safe and may help people with ANCA-associated vasculitis (AAV) who are on rituximab to build better immunity against pneumococcal disease.

These are the findings of a Phase 2 clinical trial (NCT03069703) in France that tested whether bolstering the current standard vaccination schedule could induce a better immune response to infection by pneumococcus bacteria in AAV patients.

“Our study shows that using a higher dose of vaccine is safe and effective for improving the protection of patients treated with rituximab against pneumococcal pneumonia,” Benjamin Terrier, MD, a professor of medicine at Cochin Hospital, Paris Cité University, and the study’s first author, said in a press release.

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Trial findings were presented in a poster at this year’s ACR Convergence, the American College of Rheumatology’s annual meeting, which ran earlier this month in Philadelphia. The poster was titled, “Innovative Anti-pneumococcal Vaccine Strategies versus Standard Vaccination Regimen in Patients with ANCA-associated Vasculitides Receiving Rituximab Therapy: A Multicenter Randomized Controlled Trial (PNEUMOVAS).”

AAV occurs when the immune system makes autoantibodies that mistakenly target proteins found on neutrophils, overly activating them. Neutrophils are immune cells that help guard the body by traveling through the bloodstream to sites of infection, where they fight off bacteria and other possible invaders.

In the presence of AAV autoantibodies, neutrophils go awry and start attacking the cells lining blood vessels, causing inflammation.

Rituximab is a medication that helps to keep the immune system in check by causing a near-complete depletion of B-cells — immune cells that are responsible for making antibodies. Reducing the number of B-cells is expected to lower the production of the autoantibodies thought to cause inflammation in AAV. [Sold as Rituxan in the U.S. and as MabThera in Europe with biosimilars available, rituximab is approved to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two types of AAV.]

Due to its effects on immune cells, however, rituximab can place patients at a greater risk of infections, particularly those caused by pneumococcus bacteria. The medication is also known to weaken the body’s response to vaccines aiming to prevent such infections.

“There is thus a need to develop enhanced anti-pneumococcal vaccine strategies to increase immune response and protection,” the scientists wrote.

Researchers reported data from a Phase 2 trial that evaluated the safety and efficacy of two reinforced pneumococcal vaccination schemes in AAV patients using rituximab.

The study included 95 adult patients from the French Vasculitis Study Group database. All had newly diagnosed or relapsing AAV with active disease, and all were planned to receive induction therapy with rituximab for four weeks, followed by maintenance therapy every six months.

At study entry, patients were randomly assigned to one of three possible vaccination schemes.

Two types of pneumococcal vaccines are available: a pneumococcal conjugate vaccine (PCV13, PCV15, or PCV20) and a pneumococcal polysaccharide vaccine (PPV23). Both encourage the body to produce antibodies against pneumococcal bacteria,  so that the immune system will recognize contact with the bacteria in the future and fight them off more quickly.

Patients in the first group were given a standard vaccination schedule consisting of an initial dose of PCV13, also known as Prevnar 13 in the U.S. or Prevenar 13 in Europe, followed by a dose of PPV23, also known as Pneumovax 23, five months later. Those in the second group received two double doses of PCV13 given one week apart, followed by a dose of PPV23 five months later. Patients in the third group had four initial (same day) doses of PCV13, followed by a dose of PPV23 five months later.

The study’s primary goal (endpoint) was to evaluate the immune response at six months against the 12 strains of pneumococcus bacteria common to both PCV13 and PPV23.

Patients assigned to the second group were more than four times as likely as those assigned to the standard vaccination scheme (first group) to build better immune responses against these bacteria strains. Those in the third vaccination group, also reinforced, tended to have better immune responses but not significantly so.

“Our study highly suggests that patients receiving rituximab to treat an inflammatory disease could receive a higher dose of vaccine, especially two doses of PCV13 seven days apart, then PPV23 five months later, to induce a better vaccine response,” Terrier said.

“Since these patients received a high dose of glucocorticoids and rituximab, it was expected that a higher dose of vaccine was required to induce a sufficient response, but it was very important to confirm and demonstrate that,” Terrier added.

Local and systemic reactions were higher seven days after each of the higher-dose vaccine shots, as were their side effects at six months, but none were reported to be severe.

Six patients (one in the first group, two in the second group, and three in the third group) experienced flares of AAV symptoms a median of 87 days (almost three months) after vaccination.

While the study had an open-label design, “the primary outcome — the level of antibodies — was a strong endpoint that does not seem to be impacted by the lack of a double-blind [design],” Terrier said.