Stability of lyophilized Meningococcal A conjugate vaccine, (MenAfriVac™) at elevated temperatures to support controlled temperature chain (CTC) claim.

Meningococcal A Conjugate Vaccine (MenAfriVac) is the world's first Monovalent Conjugate Vaccine against Neisseria Meningitidis serogroup A which has obtained Controlled Temperature Chain (CTC) label claim of "stable upto 40°C for 4 days prior to reconstitution" developed by Serum Institute of India Pvt. Ltd. Pune, India and the vaccine was granted permission from World health Organization. This paper elucidates and talks about the layout of various studies performed to characterize the product to declare as CTC at the time when the knowledge and mechanism to describe CTC was not fully known which in term helped to design the CTC guidelines. Product stability was assessed using clinical, consistency and regular lots released by NRA. The critical stability indicating parameters like free polysaccharide, molecular size distribution along with Potency and safety tests were carried out to support the product stability making sure it also qualifies for Vaccine Vial Monitor label claim of VVM30. An additional in use stability (reconstitution) was also performed. All studies indicated that the product remains stable at real time as well as elevated temperatures and well within the specifications approved by NRA and formed the strong basis for CTC claim which is now recommended by WHO.

The importance of vaccine stockpiling to respond to epidemics and remediate global supply shortages affecting immunization: strategic challenges and risks identified by manufacturers.

While stockpiling vaccines adds another layer of complexity to vaccine manufacturing, it constitutes a crucial component of comprehensive disease preparedness and control strategies in public health management. Stockpiling provides the ability to immediately respond to epidemics, disease outbreaks, vaccine shortages or stock-outs at local, regional or global levels. Some stockpiles are static, not shipped until an emergency occurs; other stockpiles are rotating with vaccines used in on-going routine immunization programmes. Programmatic use indicates which vaccines to stockpile, the nature of the stockpile and the amount of vaccine to be held at any time. For immediate shipment, fully released product must be stockpiled with the challenge of monitoring remaining shelf-life requirements and the potential risk of expiry. Existing stockpiles are managed and financed globally under the purview of international organizations in the global immunization community, except for buffer stocks held by manufacturers for short periods. The added challenges to manufacturers of stockpiling vaccines, including storage, human resources and other related costs including vaccine destruction when no longer useable, needs to be recognized. This is all the more so with the likelihood of vaccine stockpiling becoming more prominent with changing disease patterns due to climate change and population movements, as well as the significant investment in the research and development of new epidemic prevention vaccines. While vaccine stockpiles managed and financed globally provide rapid response to country requests, more attention is needed in the future to ways that vaccine stockpiling can be brought under the direct purview of individual countries or regional groupings.

Quantitation of novel pentavalent meningococcal polysaccharide conjugate vaccine (Men A-TT, Men C-CRM, Men Y-CRM, Men W-CRM, Men X-TT) using sandwich ELISA.

Meningococcal vaccines have been developed over the years, to control outbreaks of meningitis. There are 12 immunologically distinct serogroups of which, A, B, C, W, Y and X are predominant and invasive in nature. Meningococcal vaccines can be sorted out as, polysaccharide vaccines, polysaccharide protein conjugate vaccines or protein based (independent of polysaccharides) vaccines. Stringent quality control analysis as per the regulatory guidelines is a requirement for any vaccine manufacturer for commercial release of vaccines. Quantitation becomes challenging when it comes to analysis of multivalent vaccines. We describe the quantitation of novel pentavalent meningococcal polysaccharide conjugate vaccine manufactured at Serum Institute of India Pvt Ltd (SIIPL). Briefly, sandwich ELISA assay was developed to quantitate five different serogroups (Men A-TT, Men C-CRM, Men Y-CRM, Men W-CRM, Men X-TT) in pentavalent meningococcal polysaccharide conjugate vaccine containing two different carrier proteins (TT and CRM). ELISA reported herein showed significant reproducibility and repeatability over a range of developed standard curve with acceptable coefficient of variation (<15%) for both intra and inter assay. Furthermore analysis showed that, polysaccharide conjugate (PC) contents were within the accepted range (±30%) of the stated label claim. The immunoassay was verified for its sensitivity, accuracy and precision. Based on the relevant experimental data; it is proposed that, reported sandwich ELISA is well suited for quantitation of individual polysaccharide conjugate from pentavalent formulation. Furthermore, the ELISA was explored for forced degradation and polysaccharide spiking studies. This leads to open up an area of research for sandwich ELISA as a tool to assess the integrity of vaccine as well as for lot to lot consistency monitoring.

Emerging manufacturers engagements in the COVID -19 vaccine research, development and supply.

The World Health Organization declared the COVID-19 disease as a pandemic requiring a rapid response. Through online search, direct communication with network members and an internal survey, engagements of developing countries' vaccine manufacturers' network members in the research and development of COVID-19 vaccines and their capacities in the manufacturing, fill-finish and distribution of vaccines were assessed. Currently, 19 network members engaged in research and development of COVID-19 vaccines, using six principal technology platforms. In addition, an internal survey showed that the number of vaccines supplied collectively by 37 members, in 2018-19, was about 3.5 billion doses annually. Almost a third of network members having vaccines prequalified by the World Health Organization comply with international regulations and mechanisms to distribute vaccines across borders. The use of existing manufacturing, fill-finish and distribution capabilities can support an efficient roll-out of vaccines against COVID-19, while maintaining supply security of existing vaccines for on-going immunization programmes.

Developmental strategy for a new Group A meningococcal conjugate vaccine (MenAfriVacR).

Until recently, periodic Group A meningococcal meningitis outbreaks were a major public health problem in the sub-Saharan Africa. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, a Seattle-based NGO, and the Serum Institute of India Pvt Ltd (SIIPL) initiated discussions aimed at establishing a collaboration to develop a Group A meningococcal conjugate vaccine for this unmet medical need. Over the next 8 years the partnership made countless strategic decisions about product characteristics, raw materials, potential target populations, geographic prioritization and affordability of the vaccine to name a few. These decisions evolved into detailed plans for preclinical development, extensive field trials in Africa and India and a focused regulatory strategy specific for the Men A conjugate vaccine. Important characteristics of the process included, flexibility, transparency andeffective partnerships that included public agencies as well as private companies in Africa, Europe, the United States and India.

Development and application of HPLC-RI and HPLC-MS/MS based methods for quantification of residual deoxycholate levels in pneumococcal polysaccharides.

The analysis of residual sodium deoxycholate (DOC); a detergent of biological origin used in manufacturing of polysaccharide vaccines is challenging due to complex sample matrices and the lack of suitable methods. Here we report, rapid and sensitive high-performance liquid chromatography-refractive index (HPLC-RI) and tandem mass spectrometry (HPLC-MS/MS) methods for estimation of residual DOC in pneumococcal polysaccharides. For HPLC-RI method, separation was achieved using Luna C18 column and mobile phase compositions of acetonitrile: methanol: 20 mM sodium acetate (60:05:35% v/v). For HPLC-MS/MS method, separation was achieved using a Hypersil BDS C18 column with gradient elution of methanol and water (0.1% formic acid). MS/MS method showed linearity (r2 = 0.997) over the range of 10-320 ng/mL with limits of detection (LOD) and lower limit of quantitation (LOQ) of 3 and 10 ng/mL respectively. Precision (% RSD) and accuracy (% recovery) for both methods were in the range of 0.74-8.29% and 82.33-117.86% respectively. Sample matrices interferences were addressed following novel sample clean-up method based on liquid-liquid extraction. Both methods enabled traceable quantitation of DOC in intermediate and purified pneumococcal polysaccharides of serotypes: 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F.

Regulatory Pathways That Facilitated Timely Registration of a New Group A Meningococcal Conjugate Vaccine for Africa's Meningitis Belt Countries.

BACKGROUND: Through its normative and public health leadership roles, the World Health Organization (WHO) plays a key role in the availability of vaccine products in low-and middle-income countries. The recent introduction of a new group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), in Africa exemplifies this process. WHO requires that any new vaccine to be introduced in countries for public health reasons and supplied through United Nations centralized mechanisms be licensed by the national regulatory agency (NRA) in the producing country, then prequalified and given a marketing authorization in the user countries. METHODS: PsA-TT was manufactured by the Serum Institute of India, Ltd (SIIL), which submitted a license application in April 2009 to the Drug Controller General of India (DCGI), the Indian NRA responsible for licensing vaccines. WHO encouraged the DCGI to establish a collaboration with Health Canada's Centre for Vaccine Evaluation for the review. Through this collaborative effort, registration was facilitated and in December 2009 an export license was granted to SIIL, which subsequently submitted an application for WHO prequalification. RESULTS: Given the importance of the vaccine, WHO "fast tracked" the prequalification review, and after a detailed review and site visit, WHO prequalification was granted to PsA-TT in June 2010. Country use of the new vaccine could not occur until the vaccine was a registered product in each country seeking its use. WHO facilitated country reviews by conducting regulatory training exercises (in French and English) for country NRA staff, which used the PsA-TT registration as a case study. CONCLUSIONS: PsA-TT was gradually registered in African countries as vaccine introduction proceeded. The regulatory pathway for this new group A meningococcal conjugate vaccine proved to be a useful training opportunity both in India and Africa, because the availability of the vaccine was a high African public health priority, as well as for WHO as a case study to facilitate registration of vaccines based on reliance on other regulatory bodies.

Challenges and Opportunities While Developing a Group A Meningococcal Conjugate Vaccine Within a Product Development Partnership: A Manufacturer's Perspective From the Serum Institute of India.

BACKGROUND: In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as its manufacturing partner to establish a product development partnership (PDP) with the Meningitis Vaccine Project (MVP). MVP was a collaboration between PATH and the World Health Organization (WHO) to develop meningococcal conjugate vaccines for sub-Saharan Africa. METHOD: From the outset, SIIL recognized that a partnership with MVP carried some risk but also offered important opportunities for accessing new conjugate vaccine technology and know-how. Over 3 years, SIIL successfully accepted technology transfer for the group A meningococcal polysaccharide from SynCo Bio Partners and a conjugation method from the US Food and Drug Administration. RESULTS: SIIL successfully scaled up production of a group A meningococcal conjugate vaccine that used SIIL tetanus toxoid as the carrier protein. Phase 1 studies began in India in 2005, followed by phase 2/3 studies in Africa and India. A regulatory dossier was submitted to the Indian authorities in April 2009 and WHO in September 2009. Export license was granted in December 2009, and WHO prequalification was obtained in June 2010. Vaccine was introduced at public scale in Burkina Faso that December. The group A meningococcal conjugate vaccine was named MenAfriVac, and is the first internationally qualified vaccine developed outside of big pharma. CONCLUSIONS: The project proved to be a sound investment for SIIL and is a concrete example of the potential for PDPs to provide needed products for resource-poor countries.

Omega-3-fatty acid adds to the protective effect of flax lignan concentrate in pressure overload-induced myocardial hypertrophy in rats via modulation of oxidative stress and apoptosis.

Objective of the present investigation was to study the effect of the flax lignan concentrate (FLC) and Omega-3-fatty acid (O-3-FA) on myocardial apoptosis, left ventricular (LV) contractile dysfunction and electrocardiographic abnormalities in pressure overload-induced cardiac hypertrophy. The rats were divided into five groups such as sham, aortic stenosis (AS), AS+FLC, AS+O-3-FA and AS+FLC+O-3-FA. Cardiac hypertrophy was produced in rats by abdominal aortic constriction. The rats were treated with FLC (400mg/kg, p.o.), O-3-FA (400mg/kg, p.o.) and FLC+O-3-FA orally per day for four weeks. The LV function, myocardial apoptosis, and oxidative stress were quantified. FLC+O-3-FA treatment significantly reduced hemodynamic changes, improved LV contractile dysfunction, reduced cardiomyocyte apoptosis and cellular oxidative stress. Moreover, it significantly up-regulated the VEGF expression and decreased TNF-alpha level in serum. The histological analysis also revealed that FLC+O-3-FA treatment markedly preserved the cardiac structure and inhibited interstitial fibrosis. In conclusion, FLC+O-3-FA treatment improved LV dysfunction, inhibited cardiomyocyte apoptosis, improved myocardial angiogenesis, conserved activities of membrane-bound phosphatase enzymes and suppressed inflammation through reduced oxidative stress in an additive manner than FLC alone and O-3-FA alone treatment in pressure overload-induced cardiac hypertrophy.

Enhanced mucosal immune responses against tetanus toxoid using novel delivery system comprised of chitosan-functionalized gold nanoparticles and botanical adjuvant: characterization, immunogenicity, and stability assessment.

Approaches based on combined use of delivery systems and adjuvants are being favored to maximize efficient mucosal delivery of antigens. Here, we describe a novel delivery system comprised of chitosan-functionalized gold nanoparticles (CsAuNPs) and saponin-containing botanical adjuvant; Asparagus racemosus extract (ARE) for oral delivery of tetanus toxoid (TT). A significant increase in TT-specific IgG (34.53-fold) and IgA (43.75-fold) was observed when TT-CsAuNPs were formulated with ARE (TT-ARE-CsAuNPs). The local IgA immune responses for TT also showed a significant increase (106.5-fold in intestine washes and 99.74-fold in feces) with ARE-based formulations as compared with plain TT group. No effect of ARE was observed on size, charge, and loading properties of CsAuNPs. Additionally, no effect of ARE and CsAuNPs was observed on antigenicity and secondary structure of TT as determined by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. The stability studies demonstrated excellent stability profile of formulation at recommended storage conditions. The study establishes the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines.

Structure function attributes of gold nanoparticle vaccine association: effect of particle size and association temperature.

Many biotherapeutic applications of gold nanoparticles make use of conjugated or adsorbed protein moieties. Physical parameters of association such as particle size, morphology, surface chemistry and temperature influences the protein-nanoparticle association and thereby their interaction with the biological environment. In present study, effect of size of chitosan reduced gold nanoparticles (CsAuNPs) and association temperature on structure and function of tetanus toxoid (TT) vaccine has been investigated. CsAuNPs were synthesized in the sizes of 20±3, 40±5 and 80±7 nm followed by loading of TT. Binding process of CsAuNPs with TT was investigated at their predetermined micro molar concentrations. Upon binding of TT onto CsAuNPs, particle surface was characterized using X-ray photoelectron spectroscopy. CD spectroscopic evaluation of TT bound 20 nm CsAuNPs led to 75% reduction in secondary structure of TT and thereby compromised immune function. Binding of TT with 40 and 80 nm sized CsAuNPs did not cause significant modifications in secondary structure or function of TT. Thermodynamic studies using temperature dependent fluorescence spectroscopy revealed an increase in association constants with the temperature. Based on thermodynamic data three phases in CsAuNPs and TT association process were traced. Samples from these distinct phases were also investigated for immunological recognition. Ex-vivo interaction of TT-CsAuNPs with TT positive and negative sera followed by relative change in particle size and zeta potential was studied. The findings here suggests prominent role of particle size and association temperature on adsorbed TT structure and function. Such studies may help in engineering functional nanotherapeutics.

HPLC/tandem mass spectrometric studies on steroidal saponins: an example of quantitative determination of Shatavarin IV from dietary supplements containing Asparagus racemosus.

Asparagus racemosus (AR) is a popular botanical present in several Ayurvedic medicines and nutritional and dietary supplements with immunomodulatory, galactogogue, and anticancer activity. A steroidal saponin known as shatavarin IV is one of the active constituents of AR. A new, selective, and rapid HPLC/MSIMS method has been developed and validated for quantitative estimation of shatavarin IV in crude, processed, and marketed samples of AR. The analytes were separated on a Luna C18 column using simple isocratic elution with water (0.1% acetic acid)-acetonitrie;(0.1% acetic acid; 70 + 30, vIv) at a flow rate of 0.8 mLlmin. The analytes were detected by electrospray ionization (ESI)-MS/MS and quantified using multiple reaction monitoring techniques in the positive ion mode. The method showed excellent linearity (r2 > 0.998) over the concentration range of 7.5 to 254 ng/mL with LOD of 2.5 ng/mL. Precision (RSD) and accuracy (recovery) were found in the ranges of 2.00 to 5.15 and 102 to 110%, respectively. The validated HPLC/ESI-MS/MS method was successfully applied to the quantification of shatavarin IV in crude, processed, and marketed (single or multiherb) AR samples. Therefore, this method could be used for QC and standardization of pharmaceutical or nutritional products containing AR.

Effect of botanical immunomodulators on human CYP3A4 inhibition: implications for concurrent use as adjuvants in cancer therapy.

PURPOSE: Many botanical immunomodulators are used as adjuvants along with cancer chemotherapy. However, information on the impact of concurrent administration of such botanicals on pharmacokinetics of chemotherapy agents is inadequate. This study investigates inhibitory activities of 3 popular botanical adjuvants: ASPARAGUS RACEMOSU: (root aqueous extract; ARE), WITHANIA SOMNIFER: (root aqueous extract; WSE), and TINOSPORA CORDIFOLI: (stem aqueous extract, TCE) on human CYP3A4 isoenzyme, responsible for metabolism of several chemotherapy agents. EXPERIMENTAL DESIG: . Testosterone 6-ß hydroxylation was monitored using high-performance liquid chromatography as an indicator of CYP3A4 catalytic activities. Ketoconazole (positive control) and extracts were studied at their in vivo-relevant concentrations. RESULTS: TCE showed mild inhibition while no significant inhibitory activities were observed in WSE and ARE. TCE was further fractionated to obtain polar and nonpolar fractions. The nonpolar fraction showed significant CYP3A4 inhibition with IC50 13.06 ± 1.38 µg/mL. Major constituents of nonpolar fraction were identified using HPLC-DAD-MS profiling as berberine, jatrorrhizine, and palmatine, which showed IC50 values as 6.25 ± 0.30, 15.18 ± 1.59, and 15.53 ± 1.89 µg/mL, respectively. CONCLUSION: Our findings suggest that constituents of TCE extract especially protoberberine alkaloids have the potential to interact with cancer chemotherapy agents that are metabolized by CYP3A4 in vivo.

Developing Countries Vaccine Manufacturers Network (DCVMN): engaging to step up for vaccine discovery and access. Meeting report 2012.

At the annual general meeting of the Developing Countries Vaccine Manufacturers Network (DCVMN) members renewed their engagement and cooperative spirit in pursuing the mission of increasing the quality and availability of affordable vaccines for all people. Thirteen years after its establishment, DCVMN moves into the Decade of Vaccines with renewed dynamism and synergy to create greater impact and shape the global and regional vaccination landscape, while supporting national growth. The DCVMN is growing: 12 new members joined in 2012, making a total of 37 members from 14 countries; 9 of these 37 manufacturers make WHO-prequalified vaccines. More than one hundred and forty delegates from 23 countries attended the annual general meeting, representing 24 vaccine manufacturers and leaders of 20 major global health institutions. Over the course of two days, delegates exchanged information and ideas on how to jointly achieve the common goal of protecting people against known and emerging infectious diseases. In an increasingly complex environment of new technologies, demanding regulatory requirements, higher cost of production, and a growing number of legal and intellectual property issues, it is observed that many manufacturers and stakeholders are engaged in technology transfer initiatives. This well-attended meeting highlighted the growing impact and important contributions of developing country vaccine manufacturers in shaping the global vaccine landscape. The successful introduction of the first ever vaccine against hepatitis E and of a new vaccine against meningitis A, tailored for African meningitis belt countries, illustrate the innovative capacity of DCVMN members. An increase in the variety of collaborations, partnerships and alliances between DCVM and various institutions was observed. Interestingly, bilateral technology transfer partnerships between DCVMs themselves are on the rise.

Developing Countries Vaccine Manufacturers Network: doing good by making high-quality vaccines affordable for all.

The Developing Countries Vaccine Manufacturers Network (DCVMN) is a unique model of a public and private international alliance. It assembles governmental and private organizations to work toward a common goal of manufacturing and supplying high-quality vaccines at affordable prices to protect people around the world from known and emerging infectious diseases. Together, this group of manufacturers has decades of experience in manufacturing vaccines, with technologies, know-how, and capacity to produce more than 40 vaccines types. These manufacturers have already contributed more than 30 vaccines in various presentations that have been prequalified by the World Health Organization for use by global immunization programmes. Furthermore, more than 45 vaccines are in the pipeline. Recent areas of focus include vaccines to protect against rotavirus, human papillomavirus (HPV), Japanese encephalitis, meningitis, hepatitis E, poliovirus, influenza, and pertussis, as well as combined pentavalent vaccines for children. The network has a growing number of manufacturers that produce a growing number of products to supply the growing demand for vaccines in developing countries.

Determination of withaferin A and withanolide A in mice plasma using high-performance liquid chromatography-tandem mass spectrometry: application to pharmacokinetics after oral administration of Withania somnifera aqueous extract.

Withania somnifera (WS) is one of the popular botanical medicines widely used in Ayurveda. Withanolides such as withaferin A (WA) and withanolide A (WLD) are its bioactive constituents reported as promising drug candidates in cancer and neurological disorders respectively. A new, selective and rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for simultaneous determination of WA and WLD in mice plasma. Simple liquid-liquid extraction procedure was followed using ter-butyl methyl ether (TBME) for plasma sample pretreatment. Analytes were separated on Hypurity C18 column using methanol and ammonium acetate (95:5, v/v) as a mobile phase and detected by electrospray ionization in the multiple reaction monitoring (MRM) mode. The mass transition ion-pair was followed as m/z 471.3→281.2 for WA; m/z 437.2→292.2 for tianeptine (IS) and m/z 488.3→263.1 for WLD; m/z 315.9→270 for clonazepam (IS). The method showed excellent linearity (r(2)>0.997) over the concentration range of 0.484-117.880ng/ml for WA and from 0.476-116.050ng/ml for WLD. The lower limits of quantification (LLOQs) were found to be 0.484ng/ml and 0.476ng/ml for WA and WLD respectively. Precision (% CV) and accuracy (% bias) were found in the range of 3.7-14.3% and -14.4-4.0%, respectively. The validated method was successfully applied to a pharmacokinetic (PK) study for estimation of WA and WLD in mice plasma following oral administration of W. somnifera root aqueous extract (WSE). The PK study suggested rapid oral absorption of these withanolides. The PK study revealed that withaferin A has one and half times more relative bioavailability as compared to withanolide A.

Quillaja saponaria extract as mucosal adjuvant with chitosan functionalized gold nanoparticles for mucosal vaccine delivery: stability and immunoefficiency studies.

Carrier mediated delivery of vaccines along with adjuvants can possibly address the issue related to oral vaccines like inadequate immune potentiation. In this study, chitosan functionalized gold nanoparticles (CsAuNPs) were used as a carrier for the model antigen tetanus toxoid (TT) along with immunostimulant Quillaja saponaria extract (QS). Physicochemical properties (size, zeta potential, pH value) of formulation were investigated as stability indicating parameters. The synthesized CsAuNPs were spherical in shape, around 40 nm in size, positively charged (around +35 mV) and had TT and QS payload of 65% and 0.01%, respectively. Formulation parameters did not alter the secondary structure of TT, as determined by FTIR, fluorescence and CD spectroscopy. Antigen specificity, determined by an ELISA, was also not compromised. The CsAuNPs conferred protection to TT against gastric hydrolysis as studied in vitro. TT-QS-CsAuNPs induced up to 28-fold immune responses compared to control formulations (TT, TT-QS) after oral administration of formulations in BALB/c mice. The immune responses were quantified by measuring the TT-specific IgG and IgA titers using ELISA. Findings herein demonstrate that co-delivery of TT and QS with functionalized CsAuNPs promotes better systemic and local immune responses and hence can be considered as a sound approach for oral vaccine delivery.

Antibody persistence of two pentavalent DTwP-HB-Hib vaccines to the age of 15-18 months, and response to the booster dose of quadrivalent DTwP-Hib vaccine.

OBJECTIVES: Antibody persistence in children following three doses of primary vaccination with diphtheria, tetanus, whole-cell-pertussis (DTwP), hepatitis B, and Haemophilus influenzae type b (Hib) vaccines (SIIL Pentavac vaccine vs. Easyfive(®) of Panacea Biotec), and response to the booster dose of DTwP-Hib (Quadrovax(®)) vaccine. METHODS: Children who completed their primary immunization were assessed for antibodies at 15-18 months of age, and then given a booster dose of DTwP-Hib vaccine. Reactogenicity and safety of the booster dose was evaluated. RESULTS: Both pentavalent vaccines demonstrated a good immune response at 15-18 months. Following the booster dose, all vaccinated subjects achieved protective titers against diphtheria, tetanus and Hib, whereas the response to pertussis antigen was ~78%. Fever and irritability was noted in 24%, local pain in 51%, and swelling in 36% of the children following booster dose. CONCLUSIONS: Primary immunization with either pentavalent vaccine induced an excellent immunity lasting till the second year of life. A booster dose with DTwP-Hib (Quadrovax(®)) vaccine effectuated a good anamnestic response to all vaccine components, being specially strong for Hib in children previously vaccinated with SIIL liquid pentavalent vaccine (Pentavac(®)). Also, the safety profile of SIIL quadrivalent vaccine (Quadrovax(®)) administered as booster dose was acceptable.

An evaluation of the emerging vaccines against influenza in children.

BACKGROUND: Influenza is an under-appreciated cause of acute lower respiratory infections (ALRI) in children. It is estimated to cause approximately 20 million new episodes of ALRI in children annually, 97% of these occurring in developing countries. It is also estimated to result in 28000 to 112000 deaths annually in young children. Apart from hospitalisations and deaths, influenza has significant economic consequences. The current egg-based inactivated influenza vaccines have several limitations: annual vaccination, high production costs, and cannot respond adequately to meet the demand during pandemics. METHODS: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging cross-protective vaccines against influenza relevant to several criteria of interest: answerability; cost of development, production and implementation; efficacy and effectiveness; deliverability, affordability and sustainability; maximum potential impact on disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from the CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%. RESULTS: The experts expressed very high level of optimism for deliverability, impact on equity, and acceptability to health workers and end users. However, they expressed concerns over the criteria of answerability, low development cost, low product cost, low implementation cost, affordability and, to a lesser extent sustainability. In addition they felt that the vaccine would have higher efficacy and impact on disease burden reduction on overall influenza-associated disease rather than specifically influenza-associated pneumonia. CONCLUSION: Although the landscape of emerging influenza vaccines shows several promising candidates, it is unlikely that the advancements in the newer vaccine technologies will be able to progress through to large scale production in the near future. The combined effects of continued investments in researching new vaccines and improvements of available vaccines will hopefully shorten the time needed to the development of an effective seasonal and pandemic influenza vaccine suitable for large scale production.