WHO Prequalification Research Articles

REASSURED evaluation of the Bioline HCV point-of-care testing for diagnosing hepatitis C virus infection in primary healthcare settings of Ghana: a study protocol

IntroductionHepatitis C virus (HCV) infection is a silent epidemic that needs a comprehensive and contextualised approach to manage. Access to readily available, affordable and acceptable HCV point-of-care (POC) in vitro...

Defining a malaria diagnostic pathway from innovation to adoption: Stakeholder perspectives on data and evidence gaps.

Malaria, a major global health concern, requires effective diagnostic tools for patient care, disease control, and elimination. The pathway from concept to the adoption of diagnostic products is complex, involving multiple steps and stakeholders. To map this process, our study introduces a malaria-specific diagnostic pathway, synthesising existing frameworks with expert insights. Comprising six major stages and 31 related activities, the pathway retains the core stages from existing frameworks and integrates essential malaria diagnostic activities, such as WHO prequalification processes, global stakeholder involvement, and broader health systems considerations. To understand the scope and availability of evidence guiding the activities along this pathway, we conducted an online survey with 113 participants from various stages of the malaria diagnostic pathway. The survey assessed perceptions on four critical attributes of evidence: clear requirements, alignment with user needs, accuracy and reliability, and public and free availability. It also explored the types of evidence used and the challenges and potential solutions related to evidence generation and use. Respondents reported using a broad range of formal and informal data sources. Findings indicated differing levels of agreement on the attributes across pathway stages, with notable challenges in the Approvals and Manufacturing stage and consistent concerns regarding the public availability of data/evidence. The study offers valuable insights for optimising evidence generation and utilisation across the malaria diagnostic pathway. It highlights the need for enhanced stakeholder collaboration, improved data availability, and increased funding to support effective evidence generation, sharing, and use. We propose actionable solutions, including the use of public data repositories, progressive data sharing policies, open-access publishing, capacity-building initiatives, stakeholder engagement forums, and innovative funding solutions. The developed framework and study insights have broader applications, offering a model adaptable for other diseases, particularly for neglected tropical diseases, which face similar diagnostic challenges.

Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to

Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification. This phase 3 trial recruited infants aged 18 to <52 weeks and young children aged 1 to <5 years in The Gambia. Infants randomly assigned to receive one or two doses of one of three lots of nOPV2 or one lot of bivalent OPV (bOPV). Young children were randomised to receive two doses of nOPV2 lot 1 or bOPV. The primary immunogenicity objective was to assess lot-to-lot equivalence of the three nOPV2 lots based on one-dose type 2 poliovirus neutralising antibody seroconversion rates in infants. Equivalence was declared if the 95% CI for the three pairwise rate differences was within the -10% to 10% equivalence margin. Tolerability and safety were assessed based on the rates of solicited adverse events to 7 days, unsolicited adverse events to 28 days, and serious adverse events to 3 months post-dose. Stool poliovirus excretion was examined. The trial was registered as PACTR202010705577776 and is completed. Between February and October, 2021, 2345 infants and 600 young children were vaccinated. 2272 (96·9%) were eligible for inclusion in the post-dose one per-protocol population. Seroconversion rates ranged from 48·9% to 49·2% across the three lots. The minimum lower bound of the 95% CIs for the pairwise differences in seroconversion rates between lots was -5·8%. The maximum upper bound was 5·4%. Equivalence was therefore shown. Of those seronegative at baseline, 143 (85·6%) of 167 (95% CI 79·4-90·6) infants and 54 (83·1%) of 65 (71·7-91·2) young children seroconverted over the two-dose nOPV2 schedule. The post-two-dose seroprotection rates, including participants who were both seronegative and seropositive at baseline, were 604 (92·9%) of 650 (95% CI 90·7-94·8) in infants and 276 (95·5%) of 289 (92·4-97·6) in young children. No safety concerns were identified. 7 days post-dose one, 78 (41·7%) of 187 (95% CI 34·6-49·1) infants were excreting the type 2 poliovirus. nOPV2 was immunogenic and safe in infants and young children in The Gambia. The data support the licensure and WHO prequalification of nOPV2. Bill & Melinda Gates Foundation.

One billion doses and WHO prequalification of nOPV2: Implications for the global polio situation and beyond

One billion doses and WHO prequalification of nOPV2: Implications for the global polio situation and beyond

Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial

Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

Tolerability, safety, and immunogenicity of the novel oral polio vaccine type 2 in children aged 6 weeks to 59 months in an outbreak response campaign in The Gambia: an observational cohort study

Novel oral polio vaccine type 2 (nOPV2) has been used to interrupt circulating vaccine-derived poliovirus type 2 outbreaks following its WHO emergency use listing. This study reports data on the safety and immunogenicity of nOPV2 over two rounds of a campaign in The Gambia. This observational cohort study collected baseline symptoms (vomiting, diarrhoea, irritability, reduced feeding, and reduced activity) and axillary temperature from children aged 6 weeks to 59 months in The Gambia before a series of two rounds of a nOPV2 campaign that took place on Nov 20-26, 2021, and March 19-22, 2022. Serum and stool samples were collected from a subset of the participants. The same symptoms were re-assessed during the week following each dose of nOPV2. Stool samples were collected on days 7 and 28, and serum was collected on day 28 following each dose. Adverse events, including adverse events of special interest, were documented for 28 days after each campaign round. Serum neutralising antibodies were measured by microneutralisation assay, and stool poliovirus excretion was measured by real-time RT-PCR. Of the 5635 children eligible for the study, 5504 (97·7%) received at least one dose of nOPV2. There was no increase in axillary temperature or in any of the baseline symptoms following either rounds of the campaigns. There were no adverse events of special interest and no other safety signals of concern. Poliovirus type 2 seroconversion rates were 70% (95% CI 62 to 78; 87 of 124 children) following one dose of nOPV2 and 91% (85 to 95; 113 of 124 children) following two doses. Poliovirus excretion on day 7 was lower after the second round (162 of 459 samples; 35·3%, 95% CI 31·1 to 39·8) than after the first round (292 of 658 samples; 44·4%, 40·6 to 48·2) of the campaign (difference -9·1%; 95% CI -14·8 to -3·3), showing the induction of mucosal immunity. In a campaign in west Africa, nOPV2 was well tolerated and safe. High rates of seroconversion and evidence of mucosal immunity support the licensure and WHO prequalification of this vaccine. Bill & Melinda Gates Foundation.

Phase III randomized clinical studies to evaluate the immunogenicity, lot-to-lot consistency, and safety of ROTAVAC® liquid formulations (ROTAVAC 5C & 5D) and non-inferiority comparisons with licensed ROTAVAC® (frozen formulation) in healthy infants

ABSTRACT The WHO pre-qualified rotavirus vaccine, ROTAVAC®, is derived naturally from the neonatal 116E rotavirus strain, and stored at −20°C. As refrigerator storage is preferable, immunogenicity and safety of liquid formulations kept at 2–8°C, having excipients to stabilize the rotavirus, with or without buffers, were compared with ROTAVAC® in different clinical studies. Study-1, the pivotal trial for this entire product development work, was a randomized, single-blind trial with two operationally seamless phases: (i) an exploratory phase involving 675 infants in which two formulations, ROTAVAC 5C (LnHRV-1.5 mL and LnHRV-2.0 mL) containing buffer and excipients to stabilize the virus against gastric acidity and temperature, were compared with ROTAVAC®. As the immune response of ROTAVAC 5C (LnHRV-2.0 mL) was non-inferior to ROTAVAC®, it was selected for (ii) confirmatory phase, involving 1,302 infants randomized 1:1:1:1 to receive three lots of LnHRV-2.0 mL, or ROTAVAC®. Primary objectives were the evaluation of non-inferiority and lot-to-lot consistency. The secondary objectives were to assess the safety and interference with the concomitant pentavalent vaccine. As it was separately established that buffers are not required for ROTAVAC®, in Study-2, the safety and immunogenicity of ROTAVAC 5D® (with excipients) were compared with ROTAVAC® and lot-to-lot consistency was assessed in another study. All lots elicited consistent immune responses, did not interfere with UIP vaccines, and had reactogenicity similar to ROTAVAC®. ROTAVAC 5C and ROTAVAC 5D® were immunogenic and well tolerated as ROTAVAC®. ROTAVAC 5D® had comparable immunogenicity and safety profiles with ROTAVAC® and can be stored at 2–8°C, leading to WHO pre-qualification. Clinical Trials Registration: Clinical Trials Registry of India (CTRI): CTRI/2015/02/005577CTRI/2016/11/007481 and CTRI/2019/03/017934.

Strengthening clinical development activities and preparedness for vaccine manufacturers from emerging countries: Results of a survey.

Vaccine development, in most cases, is a long, complex process, often lasting years and involving a combination of public and private stakeholders. Particularly, the vaccine clinical development process is highly regulated by several guidelines, regulatory pathways and science-based recommendations from experts. Designing and executing a successful clinical development plan for any candidate vaccine requires a solid scientific, medical, operational and regulatory knowledge and expertise, to comply with regulations and assure adequate benefit-risk balance for the product to be used in mass vaccination of healthy populations. The purpose of this study was to assess the approaches and practices related to Clinical Development functions, and related activities among vaccine manufacturers based in emerging countries, and to identify industry needs in terms of organizational development and training needs. A structured questionnaire designed specifically for assessing indicators of clinical activities, in the last five years, comprised of four sections aimed to collect information on (1) the organizational structure and the activities conducted by the clinical functions; (2) the clinical trial design ability and the management of clinical trial documents; (3) the clinical trial management and monitoring activities; (4) the quality aspects of clinical activities. The results suggest that the great majority of respondents is engaged in intense clinical development activities, as indicated by the high number of licensed vaccines available and supplied in the national markets or in foreign markets, including vaccines with WHO prequalification status. Areas to further strengthen the clinical activities and medical research preparedness were identified. Greater engagements of stakeholders' and investments will be required to expand the clinical basis in vaccine R&D, and to support achieving a high level of preparedness in emerging countries, for development of new vaccines against future regional epidemics and global pandemics.

Assessment of serological responses following vaccination campaigns with type 2 novel oral polio vaccine: a population-based study in Tajikistan in 2021

Novel oral poliovirus vaccine type 2 (nOPV2) was used to control an outbreak of type 2 circulating vaccine derived poliovirus (cVDPV2) in Tajikistan, in 2021. We measured seroconversion and seroprevalence of type 2 polio antibodies in children who were reported to have received two doses of nOPV2 in outbreak response campaigns. In this community serosurvey, children born after Jan 1, 2016 were enrolled from seven districts in Tajikistan. Dried blood spot cards were collected before nOPV2 campaigns and after the first and second rounds of the campaigns and were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) for microneutralisation assay to determine presence of polio antibodies. The primary endpoint was to assess change in seroprevalence and seroconversion against poliovirus serotype 2 after one and two doses of nOPV2. 228 (97%) of 236 enrolled children were included in the analysis. The type 2 antibody seroprevalence was 26% (53/204; 95% CI 20 to 33) before nOPV2, 77% (161/210; 70 to 82) after one dose of nOPV2, and 83% (174/209; 77 to 88) after two doses of nOPV2. The increase in seroprevalence was statistically significant between baseline and after one nOPV2 dose (51 percentage points [42 to 59], p<0·0001), but not between the first and second doses (6 percentage points [-2 to 15], p=0·12). Seroconversion from the first nOPV2 dose, 67% (89/132; 59 to 75), was significantly greater than that from the second nOPV2 dose, 44% (20/45; 30 to 60; χ2 p=0·010). Total seroconversion after two nOPV2 doses was 77% (101/132; 68 to 83). Our study demonstrated strong immune responses following nOPV2 outbreak response campaigns in Tajikistan. Our results support previous clinical trial data on the generation of poliovirus type 2 immunity by nOPV2 and provide evidence that nOPV2 can be appropriate for the cVDPV2 outbreak response. The licensure and WHO prequalification of nOPV2 should be accelerated to facilitate wider use of the vaccine. World Health Organization, Centers for Disease Control and Prevention, and Rotary International.

Lot-to-lot consistency of a hexavalent DTwP-IPV-HB-PRP∼T vaccine and non-inferiority to separate DTwP-HB-PRP∼T and IPV antigen-matching vaccines at 6–8, 10–12, and 14–16 weeks of age co-administered with oral rotavirus vaccine in healthy infants in India: A multi-center, randomized, controlled study

BackgroundCombination vaccines reduce the number of pediatric injections but must be as safe, immunogenic, and effective as each of the individual vaccines given separately. Additionally, consistency in manufacturing lots is essential for WHO prequalification. This study aimed to establish the lot-to-lot consistency of a fully liquid, hexavalent diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)-inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b (PRP-T) (DTwP-IPV-HB-PRP∼T) vaccine and to demonstrate non-inferiority to licensed DTwP-HB-PRP∼T and IPV vaccines. MethodsA Phase III, randomized, active-controlled, and open-label study was conducted at multiple centers across India. Healthy infants who had received a birth dose of oral poliovirus vaccine and hepatitis B vaccine received one of three lots of DTwP-IPV-HB-PRP∼T or separate DTwP-HB-PRP∼T and IPV vaccines at 6–8, 10–12, and 14–16 weeks of age. Oral rotavirus vaccine was co-administered at 6–8 weeks of age and 10–12/14–16 weeks of age. DTwP-IPV-HB-PRP∼T lot-to-lot consistency and non-inferiority (pooled DTwP-IPV-HB-PRP∼T) versus DTwP-HB-PRP∼T and IPV post-third dose were assessed using seroprotection rates (anti-D, anti-T, anti-HBs, anti-PRP, anti-polio 1, 2, 3) and adjusted geometric mean concentrations (anti-PT, anti-FIM). Safety was assessed by parental reports. ResultsLot-to-lot consistency was demonstrated for DTwP-IPV-HB-PRP∼T and non-inferiority versus DTwP-HB-PRP∼T and IPV was confirmed with 95% CIs for seroprotection rate differences and adjusted geometric mean concentration ratios within pre-defined clinical margins. Pooled seroprotection rate was ≥ 99.7% for anti-D ≥ 0.01 IU/mL, anti-T ≥ 0.01 IU/mL, anti-HBs ≥ 10 mIU/mL, anti-PRP ≥ 0.15 µg/mL, and anti-polio 1, 2, and 3 ≥ 8 (1/dil) and vaccine response rate was 83.9% for anti-PT and 97.7% for anti-FIM. There were no safety concerns. ConclusionsImmunogenicity of three lots of the fully liquid DTwP-IPV-HB-PRP∼T vaccine was consistent and non-inferior to licensed comparators following vaccination at 6–8, 10–12, and 14–16 weeks of age. There were no safety concerns and no evidence of any effect of co-administration with rotavirus vaccine.

Rotaviruses: From Pathogenesis to Disease Control-A Critical Review.

Since their first recognition in human cases about four decades ago, rotaviruses have remained the leading cause of acute severe dehydrating diarrhea among infants and young children worldwide. The WHO prequalification of oral rotavirus vaccines (ORV) a decade ago and its introduction in many countries have yielded a significant decline in the global burden of the disease, although not without challenges to achieving global effectiveness. Poised by the unending malady of rotavirus diarrhea and the attributable death cases in developing countries, we provide detailed insights into rotavirus biology, exposure pathways, cellular receptors and pathogenesis, host immune response, epidemiology, and vaccination. Additionally, recent developments on the various host, viral and environmental associated factors impacting ORV performance in low-and middle-income countries (LMIC) are reviewed and their significance assessed. In addition, we review the advances in nonvaccine strategies (probiotics, candidate anti-rotaviral drugs, breastfeeding) to disease prevention and management.

Vaccine Licensure

Vaccines must meet the highest standards for safety and efficacy, as they are used for prevention of diseases in healthy subjects, not as treatment for disease. Vaccines are biological products (live or inactivated whole microorganisms or extracts thereof, sometimes heterogenous composition, sensitive to manufacturing conditions, etc.), and thus by their nature they are different from other medicines. The licensing process itself – from development and manufacturing to evaluation of safety and effectiveness post licensure – are the product: “Development and production processes are the licensed product.” In the USA, licensing granted by the FDA encompasses two phases: an “Investigational New Drug” (IND-) phase” and a “Biologics License Application (BLA-) phase” with defined timelines and procedures. There are several ways to accelerate vaccine development and licensing if it is of high public health interest. To support licensure, efficacy must usually be shown by disease reduction in high-quality randomized controlled clinical trials (RCTs). Alternatively, licensure can be obtained based on RCTs using a validated “correlate of protection”, or animal studies if human clinical studies are not feasible. A “surrogate of protection” that is reasonably likely to predict clinical benefit may be used to support conditional licensure under the Accelerated Approval pathway with a commitment to conduct a clinical endpoint efficacy study as a post-approval commitment. For the European Union (EU) and the three European Economic Area (EEA) states, the European Medicines Agency (EMA) is responsible for vaccine licensure. Here vaccines can be licensed by a (1) Centralized Procedure, (2) Mutual Recognition, (3) Decentralized Procedure, or (4) National Procedure. In addition, for licensed vaccines, “WHO prequalification” offers a way to provide existing affordable, safe, and effective vaccines to resource-poor countries.

Safety and immunogenicity of the Vi-DT typhoid conjugate vaccine in healthy volunteers in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial

Safety and immunogenicity of the Vi-DT typhoid conjugate vaccine in healthy volunteers in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial

Global public health security and justice for vaccines and therapeutics in the COVID-19 pandemic.

A Lancet Commission for COVID-19 task force is shaping recommendations to achieve vaccine and therapeutics access, justice, and equity. This includes ensuring safety and effectiveness harmonized through robust systems of global pharmacovigilance and surveillance. Global production requires expanding support for development, manufacture, testing, and distribution of vaccines and therapeutics to low- and middle-income countries (LMICs). Global intellectual property rules must not stand in the way of research, production, technology transfer, or equitable access to essential health tools, and in context of pandemics to achieve increased manufacturing without discouraging innovation. Global governance around product quality requires channelling widely distributed vaccines through WHO prequalification (PQ)/emergency use listing (EUL) mechanisms and greater use of national regulatory authorities. A World Health Assembly (WHA) resolution would facilitate improvements and consistency in quality control and assurances. Global health systems require implementing steps to strengthen national systems for controlling COVID-19 and for influenza vaccinations for adults including pregnant and lactating women. A collaborative research network should strive to establish open access databases for bioinformatic analyses, together with programs directed at human capacity utilization and strengthening. Combating anti-science recognizes the urgency for countermeasures to address a global-wide disinformation movement dominating the internet and infiltrating parliaments and local governments.

Salmonella Typhi Vi polysaccharide conjugate vaccine protects infants and children against typhoid fever

The past decade has seen remarkable progress in our understanding of the scale of the global typhoid fever problem,1 the alarming emergence in south Asia of extensively drug-resistant Salmonella enterica serovar Typhi (S Typhi) threatening effective treatment,2 and the WHO prequalification of a typhoid conjugate vaccine,3 a new tool to prevent disease. In The Lancet, Firdausi Qadri and colleagues report the analysis to 18 months of follow-up of a cluster-randomised trial of the WHO prequalified S Typhi Vi polysaccharide tetanus toxoid conjugate vaccine (Vi-TT; Tybar TCV, Bharat Biotech International, Hyderabad, India) among infants and children aged 9 months to younger than 16 years in the densely populated and highly mobile urban area of Mirpur, Dhaka, Bangladesh.

Performance of rapid diagnostic tests for HCVinfection in serum or plasma.

Aim: HCV diagnosis will become the bottleneck in eliminating hepatitis C. Simple, accurateand cost-effective testing strategies are urgently needed to improve hepatitis C screening and diagnosis. Materials & methods: Performance of sevenrapid diagnostic tests (RDT) have been assessed in a large series (n = 498) of serum or plasma specimenscollected in France and in Cameroon. Results: Specificity varied from 96.1to 100%. The clinical sensitivity, compared with immunoassays as the reference, was high for all seven RDT (97.2-100%). The Multisure HCV antibody assay and OraQuick HCV rapid antibody test reached sensitivity ≥99%. Conclusion: A number of RDTmay be suitable for WHO prequalification and may be implemented in the framework of large-scale low-cost treatment programs to achieve the WHO viral hepatitis objectives by 2030.

An affordable pneumococcal conjugate vaccine after 20 years

An affordable pneumococcal conjugate vaccine after 20 years

Field evaluation of Veeralin, an alpha-cypermethrin + PBO long-lasting insecticidal net, against natural populations of Anopheles funestus in experimental huts in Muheza, Tanzania

The success of long-lasting insecticidal nets (LLIN) as the primary method for preventing malaria is threatened by pyrethroid resistance in Anopheles vectors. New generation long-lasting nets incorporating PBO synergist (piperonyl butoxide) with pyrethroid are designed to control insecticide-resistant mosquitoes. The efficacy of Veeralin® PBO LLINs was evaluated in experimental huts against wild free-flying pyrethroid-resistant Anopheles funestus (s.l.). Mosquito mortality, blood-feeding inhibition and personal protection were compared between untreated nets, standard LLINs and PBO/pyrethroid combination nets. Blood-feeding rates recorded with 20-times washed Veeralin were not significantly different from those with 20-times washed PermaNet 3.0 LLIN, a WHO Pre-Qualification Team (PQT) approved PBO/pyrethroid LLIN. This provides evidence that Veeralin LLIN provides similar blood-feeding inhibition to the standard approved LLIN and thus meets WHO PQT criteria for blood-feeding. Results show significantly higher mortality for Veeralin PBO LLINs against pyrethroid-resistant Anopheles funestus (s.l.) compared to DuraNet, a WHO PQT approved standard pyrethroid-only LLIN, both when unwashed and washed 20 times. The improved efficacy over a standard pyrethroid-only LLIN can be attributed to the effect of PBO in the Veeralin LLIN, hence meeting the Vector Control Advisory Group (VCAG) criteria for a resistance breaking LLIN.

Cost of goods sold analysis and recommendations to reduce costs of co-packaged mifepristone\u2013misoprostol for medical abortion

ObjectiveUnderstanding the price components of the mifepristone/misoprostol (combi-pack) for medical abortion to improve access is critical for identifying strategies to reduce product costs for quality-assured formulations and expanding its availability and use.MethodsWe constructed a cost of goods sold analysis using data collected from manufacturing companies in Bangladesh, China and India supported by publicly available information related to the product formulation, active pharmaceutical ingredients (API), manufacturing location, manufacturer profiles and other individual model components. Key model components were the active pharmaceutical ingredients (quality-assured or not), excipients, labour cost, operating cost and packaging.ResultsCombi-pack direct production cost ranges from US$1.08 for finished products which are not quality assured to US$3.05 for products containing quality assured active pharmaceutical ingredients, which means that with a 30% administrative fee applied to those prices, it could be made available between US$1.40 and US$3.97 depending on location, manufacturer’s profile, optimal market situation and the quality of the active pharmaceutical ingredients. The main model component impacting on the cost range is the purchase price of mifepristone active pharmaceutical ingredient and the current differential between quality-assured material supported by adequate documentation and API for which quality assurance cannot be demonstrated. Compared to India cost of goods sold is lower in Bangladesh primarily due to lower operating costs, including the cost of labour.ConclusionsIt is feasible to lower the cost of quality-assured combi-packs, through reducing mifepristone API cost and selection of the manufacturing location. However, manufacturers need to be incentivised to achieve WHO pre-qualification with a carefully built business case and require support in identifying and sourcing competitively priced material and manufacturing products to the necessary standard.

Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging.

Misoprostol is listed in the WHO essential medicines list and can be used for induction of labour, for prevention and treatment of post-partum haemorrhage, and for abortions. The compound is unstable, and substandard misoprostol preparations have been detected in low- and middle-income countries. We now investigated the stability of misoprostol tablets according to the international guidelines for stability testing of pharmaceutical products. Three brands (four batches) of misoprostol tablets were collected in Malawi and Rwanda: the originator product, a WHO-prequalified product, and a generic product without WHO prequalification. A further batch of the originator product was collected in Germany. To investigate the effect of damage to the primary packaging, additional blister strips of one sample were intentionally damaged with a needle and investigated in parallel. Samples were placed in stability chambers for six months at 40°C/75% relative humidity (RH) and at 25°C/60% RH. After 0, 1, 2, 3 and 6 months, misoprostol content was determined according to the International Pharmacopeia. At 40°C/75% RH, all samples showed a decline of misoprostol content, but four of the batches still remained within the pharmacopeial specifications, while one of the two batches of the generic product without WHO-prequalification showed a final content of 86.2% which is out of specifications. Damage to the primary packaging greatly decreased stability, resulting in a final content of only 48.2% of the declared misoprostol amount. At 25°C/60% RH all samples remained in specifications for six months, even the sample with the damaged blister. Dissolution of misoprostol remained in specifications of the pharmacopoeia for six months for all batches, except for the sample with damaged blisters stored at 40°C/75% RH. This study confirms that the stability of misoprostol tablets must be ensured by intact, good-quality primary packaging. Careful supplier qualification is required in the procurement process.