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Developing a manufacturing process to deliver a cost effective and stable liquid human rotavirus vaccine.

ABSTRACT: Despite solid evidence of the success of rotavirus vaccines in saving children from fatal gastroenteritis, more than 82 million infants worldwide still lack access to a rotavirus vaccine. The main barriers to global rotavirus vaccine coverage include cost, manufacturing capacity and suboptimal efficacy in low- and lower-middle income countries. One vaccine candidate with the potential to address the latter is based on the novel, naturally attenuated RV3 strain of rotavirus, RV3-BB vaccine administered in a birth dose strategy had a vaccine efficacy against severe rotavirus gastroenteritis of 94% at 12 months of age in infants in Indonesia. To further develop this vaccine candidate, a well-documented and low-cost manufacturing process is required. A target fully loaded cost of goods (COGs) of ≤$3.50 per course of three doses was set based on predicted market requirements. COGs modelling was leveraged to develop a process using Vero cells in cell factories reaching high titers, reducing or replacing expensive reagents and shortening process time to maximise output. Stable candidate liquid formulations were developed allowing two-year storage at 2-8 °C. In addition, the formulation potentially renders needless the pretreatment of vaccinees with antacid to ensure adequate gastric acid neutralization for routine oral vaccination. As a result, the formulation allows small volume dosing and reduction of supply chain costs. A dose ranging study is currently underway in Malawi that will inform the final clinical dose required. At a clinical dose of ≤6.3 log₁₀ FFU, the COGs target of ≤$3.50 per three dose course was met. At a clinical dose of 6.5 log₁₀ FFU, the final manufacturing process resulted in a COGs that is substantially lower than the current average market price, 2.44 USD per dose. The manufacturing and formulation processes were transferred to BioFarma in Indonesia to enable future RV3-BB vaccine production.

SUBMITTER: Hamidi A

PROVIDER: S-EPMC8062787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Video 1Cost-effective modified endoscopic vacuum therapy for GI transmural defects. Step-by-step process of manufacturing and potential advantages.1.Cut half gauze to the ideal size to cover only the fenestrated portion of the nasogastric tube (NGT).2.Wrap the gauze around the fenestrated portion of the NGT. The assistance of another person is important in this process.3.Cut the antimicrobial incise drape to match the size of the fenestrated portion of the NGT. Note that the incise drape is a very strong adhesive; therefore, 3 people are usually required to assemble it properly.4.Next, the suture is used to fix the gauze and drape to the NGT. Perform fixation of the modified sponge in 3 places. The first knot is in the proximal portion, just below the last fenestra of the NGT, as a marker of where the vacuum system starts. The second knot is at the distal end, to avoid migration of the modified sponge. The third knot is in the middle of the modified sponge, which is essential to serve as a guide during endoscopic placement. For example, in cases of defects without collection in which the sponge will be placed in an intraluminal position, it is ideal to place the vacuum system in the middle of the defect; in cases of intracavitary placement, it will work as a guide to how much of the modified sponge will be inside the collection.5.Finally, use a needle to make innumerable punctures in the modified sponge system to obtain adequate aspiration. An 18G needle is recommended because, in addition to having an adequate diameter, it is very sharp, which facilitates perforation of the modified sponge system.6.After creation of the modified endoscopic vacuum therapy, the functionality test is performed. Turn on the wall suction system, connect the distal end of the NGT to the tube of the canister connected on the wall, and place the NGT inside a bowl with a liquid solution. The aspiration of a large amount of liquid indicates proper functioning of the modified endoscopic vacuum therapy system.7.The device is then ready to be positioned endoscopically in the patient. After proper positioning, connect the NGT to the suction tube to avoid migration of the device upon removal of the scope.8.In addition to the cost-effective device as described, in our practice we also use wall suction to reduce costs associated with the use of the vacuum machine.9.Use the antimicrobial incise drape to seal the connection between the NGT and the suction tube to avoid leakage within the connection.10.Last, owing to instability of the negative wall pressure, a 20F intravenous catheter is connected to the tube to maintain a negative pressure between -75 and -150 mmHg, as confirmed by laboratory studies performed by our group.

Project description:BackgroundThe cost-effectiveness of universal rotavirus (RV) vaccination is controversial in developed countries. As a result, RV vaccination programs do not currently exist in most European countries. Hospitalization is the main driver of RV disease costs, and prematurity, low birth weight (LBW) and underlying medical conditions have been associated with RV hospitalization and complications. We investigated the cost-effectiveness of targeted RV vaccination of high-risk infants and universal RV vaccination versus no vaccination.MethodsDisease burden, mortality and healthcare costs of RV hospitalization for children with and without prematurity, LBW and congenital pathology were quantified in two hospital-based observational studies in the Netherlands. Cost-effectiveness analysis was based on an age-structured stochastic multi-cohort model of the Dutch population comparing universal RV vaccination and targeted vaccination of high-risk infants to no vaccination. The primary endpoint was the incremental cost-effectiveness ratio (ICER), with a threshold of €35,000/quality-adjusted life year (QALY) from the healthcare provider perspective. Sensitivity analyses included vaccine price and coverage, herd-immunity and QALY losses.ResultsA total of 936 children with RV infection were included. Prematurity, LBW and congenital pathology were associated with increased risks of RV hospitalization (relative risks (RR) ranging from 1.6 to 4.4), ICU admission (RR ranging from 4.2 to 7.9), prolonged hospital stay (1.5 to 3.0 excess days) and higher healthcare costs (€648 to €1,533 excess costs). Seven children succumbed due to RV complications, all belonging to the high-risk population. Targeted RV vaccination was highly cost-effective and potentially cost-saving from the healthcare provider perspective with ICERs below €20,000/QALY in all scenarios with total (undiscounted) annual healthcare costs between -€0.1 and €0.5 million/year. Results were most sensitive to mortality rates, but targeted vaccination remained highly cost-effective up to reductions of 90% compared to observed mortality. Universal RV vaccination was not considered cost-effective (mean ICER: €60,200/QALY) unless herd-immunity and caretaker QALY losses were included and vaccine prices were €60 at most (mean ICER: €21,309/QALY).ConclusionWe recommend targeted RV vaccination for high-risk infants in developed countries.

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Developing a manufacturing process to deliver a cost effective and stable liquid human rotavirus vaccine.

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