Osmoregulation, inhibitory neurotransmission and pH balance depend on chloride ion (Cl-) flux. In intestinal epithelial cells, apical Cl- channels control salt and fluid secretion and are, in turn, regulated by agonists acting through cyclic nucleotides and internal calcium ion concentration ([Ca2+]i). Recently, we found that muscarinic pretreatment prevents [Ca2+]i increases from eliciting Cl- secretion in T84 colonic epithelial cells. By studying concomitant inositol phosphate metabolism, we have now identified D-myo-inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4), as the inositol phosphate most likely to mediate this uncoupling. A novel, membrane-permeant ester prepared by total synthesis delivers Ins(3,4,5,6)P4 intracellularly and confirms that this emerging messenger does inhibit Cl- flux resulting from thapsigargin- or histamine-induced [Ca2+]i elevations.

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IntroductionPneumococcal conjugate vaccines (PCVs) have been available in Canada since 2001, with 13-valent PCV (PCV13) added to the infant routine immunization program throughout all Canadian provinces by 2011. The use of PCVs has dramatically reduced the burden of pneumococcal disease in Canada. As a result, decision-makers may consider switching from a more costly, higher-valent vaccine to a lower-cost, lower-valent vaccine in an attempt to allocate funds for other vaccine programs. We assessed the health and economic impact of switching the infant vaccination program from PCV13 to 10-valent PCV (PCV10) in the context of the Canadian health care system.MethodsWe performed a review of Canadian databases supplemented with published and unpublished data to obtain the historical incidence of pneumococcal disease and direct and indirect medical costs. Observed invasive pneumococcal disease (IPD) trends from surveillance data were used as a basis to forecast the future number of cases of IPD, pneumococcal pneumonia, and acute otitis media given a PCV13- or PCV10-based program. Costs and outcomes over 10 years were then estimated and presented in 2017 Canadian dollars discounted at 3% per year.ResultsSwitching from PCV13 to PCV10 would result in an additional 762,531 cases of pneumococcal disease over 10 years. Although PCV13 has a higher acquisition cost, switching to PCV10 would increase overall costs by over $500 million. Forecasted overall disease incidence was estimated substantially higher with PCV10 than with PCV13 primarily because of the potential reemergence of serotypes 3 and 19A. PCV13 was also cost saving compared with PCV10, even within a 5-year time horizon. Probabilistic sensitivity analysis showed that a PCV13-based program remained cost saving in all simulations.ConclusionAlthough switching to a PCV10-based infant vaccination program in Canada might result in lower acquisition costs, it would also result in higher public health cost and burden because of serotype reemergence.FundingPfizer Inc.Electronic supplementary materialThe online version of this article (10.1007/s40121-018-0206-1) contains supplementary material, which is available to authorized users.

The PCV program in Mexico has provided a significant return on investment. Sustained PCV13 use was estimated to provide the greatest healthcare and economic impact in Mexico. Changes to the pneumococcal vaccination program could result in serotype replacement and reduction in herd effects.

BackgroundThe burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP).ObjectiveTo estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects.MethodsWe developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE.ResultsScenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices.DiscussionInitiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.