Evaluation Of Vaccine Safety Research Articles

Systems biology assessment of human immune responses after seasonal trivalent inactivated influenza vaccine (P4307)

Abstract Systems biology represents a novel approach to comprehensively study the human immune response to vaccines at the global transcriptional and proteomic level. However, most systems vaccinology approaches utilize total PBMCs in their analyses. In this context, responses of underrepresented immune cell types in the blood are potentially obscured by the predominant cells in the PBMC fraction, and the contribution of PMNs is completely ignored. To investigate the contribution of individual cell types in the immune response following vaccination, we developed a rapid and efficient method for purifying large numbers of T cells, B cells, monocytes, NK cells, myeloid DCs and neutrophils from fresh venous human blood for systems vaccinology studies. This optimized protocol was applied to adult volunteers vaccinated with 2011-12 seasonal TIV. 100mL blood was obtained prior to and on days 1, 3, and 7 post-vaccination. Whole blood, PBMC and PMN fractions were subjected to phenotypic analysis by flow cytometry. Immune cells were fractionated and processed for RNA and protein extraction in a single day. RNA-Seq and quantitative proteomics were performed on purified cells in order to determine individual expression profiles. Our results show significant variation in the phenotypes and expression profiles of immune cells at each time point. This innovative systems approach is currently being utilized to evaluate vaccine safety and efficacy in an adjuvanted influenza clinical trial.

Parent perspectives on consent for the linkage of data to evaluate vaccine safety: A randomised trial of opt-in and opt-out consent

We examined parents' consent preferences and understanding of an opt-in or opt-out invitation to participate in data linkage for post-marketing safety surveillance of childhood vaccines. A single-blind parallel-group randomised controlled trial: 1129 families of babies born at a South Australian hospital in 2009 were sent information at 6 weeks post-partum, explaining data linkage of childhood immunisation and hospital records for vaccine safety surveillance, with 4 weeks to opt in or opt out by reply form, telephone, or email. At 10 weeks post-partum, 1026 (91%) parents were followed up by telephone interview. In both the opt-in (n = 564) and opt-out arms (n = 565), four-fifths of the parents recalled receiving the information (81% vs. 83%, P = 0.35), three-fifths reported reading it (63% vs. 67%, P = 0.11), but only two-fifths correctly identified the health records to be linked (43% vs. 39%, P = 0.21). Parents who actively consented (opted in) were more likely than those who passively consented (did not opt out) to recall the information (100% vs. 83%, P < 0.001), report reading it (94% vs. 67%, P < 0.001), and correctly identify the data sources (60% vs. 39%, P < 0.001). Most parents supported data linkage for vaccine safety surveillance (94%) and trusted its privacy protections (84%). Most parents wished to have minimal or no direct involvement, preferring either opt-out consent (40%) or no consent (30%). A quarter (24%) of parents indicated opt-in consent should be sought; of these, 8% requested consent prior to every use, 5% preferred to give broad consent just once and 11% preferred periodic renewal. Three-fifths of the parents gave higher priority to rapid vaccine safety surveillance (61%) rather than first seeking parental consent (21%), and one in seven was undecided (15%). Although 91% of parents reported that their babies were fully immunised (76%) or under-immunised (15%), and trusted vaccines as safe (90%), three-fifths (62%) were very or somewhat concerned about serious reactions. The context of data linkage is limited to vaccine safety surveillance. Only recall and understanding retained at 1 month post enrolment were measured. This trial demonstrates that informed consent for a population-based surveillance programme cannot realistically be achieved using mail-based opt-in and opt-out approaches. While recall and understanding of the study's purpose were better among parents who actively consented (opted in) compared with parents who passively consented (did not opt out), participation was substantially lower (21% vs. 96% respectively). Most parents appeared to have a poor understanding of data linkage for vaccine safety surveillance; nonetheless, they supported data linkage. They preferred a system utilising opt-out consent or no consent to one using opt-in consent.

Safety of Pandemic (H1N1) 2009 Monovalent Vaccines in Taiwan: A Self-Controlled Case Series Study

In Taiwan, new H1N1 monovalent vaccines without adjuvant and with MF59® adjuvant were used in the nationwide vaccination campaign beginning on November 1, 2009. From November 2009 through February 2010, the authors identified recipients of H1N1 vaccines who were diagnosed with adverse events of special interest (AESIs) in a large-linked safety database, and used the self-controlled case series (SCCS) method to examine the risk of each AESI in the 0–42 days after H1N1 vaccination. Of the 3.5 million doses of H1N1 vaccines administered and captured in the linked database, the SCCS analysis of Guillain-Barré syndrome (GBS) found an incidence rate ratio of 3.81 (95% confidence interval 0.43–33.85) within 0–42 days after nonadjuvanted H1N1 vaccination and no cases after MF59®-adjuvanted H1N1 vaccination. The risks of other AESIs were, in general, not increased in any of the predefined postvaccination risk periods and age groups. The databases and infrastructure created for H1N1 vaccine safety evaluation may serve as a model for safety, effectiveness and coverage studies of licensed vaccines in Taiwan.

Mode of Action (MoA) studies contribute to the safety evaluation of AS04 adjuvanted vaccines

Mode of Action (MoA) studies contribute to the safety evaluation of AS04 adjuvanted vaccines

Tuberculin skin test and BCG scar in children vaccinated at birth: a study from Iran

investigations and pre-clinical and clinical safety studies, may help to make informed decisions in clinical practice. Methods: Pre-clinical toxicology and clinical safety assessments, both within the context of controlled clinical trials and post-marketing surveillance, are conducted for all licensed vaccines. In addition pre-clinical adjuvant MoA studies provide additional information regarding the safety profile of novel adjuvanted vaccines. Our discussion will focus on the added support that MoA studies bring to the safety evaluation of adjuvanted vaccines. As an example of MoA and safety data wewill use the results of studies with the AS04-adjuvanted L1/16&18 HPV vaccine. Results: The preclinical toxicology package of the AS04adjuvanted L1/16&18 HPV vaccine has not shown treatmentrelated toxicologyfindings other than local injection site inflammation. MoA data showed that AS04 induced a transient and localised activation of innate cells at the injection site and in the local draining lymph nodes, with no systemic impact or direct effect on T cells and B-cellls. Clinical safety evaluation and follow-up in a trial setting have shown no clinically relevant differences compared with control groups other than reactogenicity, mostly at local level, consistent with findings from preclinical data and MoA studies. Finally, with more than 25 million doses distributed worldwide, post-licensure safety evaluations have shown adverse events consistent with what has been observed in the clinical development program, with most commonly reported events being local site reactions of short duration (2-3 days). Conclusion:Regulatory authorities require rigorouspre-clinical and clinical safety data to determine the benefit/risk profile of new vaccines. Post-licensure, a continuous pharmacovigilance system is in place to further assess vaccine safety. Research studying the mechanism of action of an adjuvanted vaccine can help to further investigate the vaccine’s safety profile.

GeVaDSs – decision support system for novel Genetic Vaccine development process

BackgroundThe lack of a uniform way for qualitative and quantitative evaluation of vaccine candidates under development led us to set up a standardized scheme for vaccine efficacy and safety evaluation. We developed and implemented molecular and immunology methods, and designed support tools for immunization data storage and analyses. Such collection can create a unique opportunity for immunologists to analyse data delivered from their laboratories.ResultsWe designed and implemented GeVaDSs (Genetic Vaccine Decision Support system) an interactive system for efficient storage, integration, retrieval and representation of data. Moreover, GeVaDSs allows for relevant association and interpretation of data, and thus for knowledge-based generation of testable hypotheses of vaccine responses.ConclusionsGeVaDSs has been tested by several laboratories in Europe, and proved its usefulness in vaccine analysis. Case study of its application is presented in the additional files. The system is available at: http://gevads.cs.put.poznan.pl/preview/(login: viewer, password: password).

Preclinical safety evaluation of DNA vaccines encoding modified HPV16 E6 and E7

Persistent infection with high-risk human papillomaviruses (hrHPV) can result in the formation of anogenital cancers. As hrHPV proteins E6 and E7 are required for cancer initiation and maintenance, they are ideal targets for immunotherapeutic interventions. Previously, we have described the development of DNA vaccines for the induction of HPV16 E6 and E7 specific T cell immunity. These vaccines consist of ‘gene-shuffled’ (SH) versions of HPV16 E6 and E7 that were fused to Tetanus Toxin Fragment C domain 1 (TTFC) and were named TTFC-E6SH and TTFC-E7SH. Gene-shuffling was performed to avoid the risk of inducing malignant transformation at the vaccination site. Here, we describe the preclinical safety evaluation of these candidate vaccines by analysis of their transforming capacity in vitro using established murine fibroblasts (NIH 3T3 cells) and primary human foreskin keratinocytes (HFKs). We demonstrate that neither ectopic expression of TTFC-E6SH and TTFC-E7SH alone or in combination enabled NIH 3T3 cells to form colonies in soft agar. In contrast, expression of HPV16 E6WT and E7WT alone or in combination resulted in effective transformation. Similarly, retroviral transduction of HFKs from three independent donors with both TTFC-E6SH and TTFC-E7SH alone or in combination did not show any signs of immortalization. In contrast, the combined expression of E6WT and E7WT induced immortalization in HFKs from all donors. Based on these results we consider it justified to proceed to clinical evaluation of DNA vaccines encoding TTFC-E6SH and TTFC-E7SH in patients with HPV16 associated (pre)malignancies.

Public perspectives on consent for the linkage of data to evaluate vaccine safety

IntroductionWe sought community opinion on consent alternatives when linking childhood immunisation and hospital attendance records for the purpose of vaccine safety surveillance. MethodsWe conducted computer-assisted telephone interviewing (CATI) of a sample of rural and metropolitan residents of South Australia in 2011. ResultsOf 2002 households interviewed (response rate 55.6%), 96.4% supported data linkage for postmarketing surveillance of vaccines; very few were completely opposed (1.5%) or undecided (2.2%). The majority (75.3%) trusted the privacy protections used in data linkage and most wished to have minimal or no direct involvement, preferring either opt-out consent (40.4%) or no consent (30.6%). A quarter of respondents (24.6%) favoured opt-in consent, but their preferences were divergent; half requested consent be sought prior to every use (11.4%) while the remainder preferred to give broad consent just once (3.4%) or renewed at periodic intervals (9.8%). Over half of the respondents gave higher priority to rapid vaccine safety surveillance (56.5%) rather than first seeking parental consent (26.6%) and one in seven was undecided (14.5%). Although 91.6% of respondents believed childhood vaccines are safe, over half (53.1%) were very or somewhat concerned that a vaccine could cause a serious reaction. Nevertheless, 92.4% of the parents in the sample (556/601) reported every child in their care as being fully immunised according to the National Immunisation Program schedule. Only 3.7% of parents (22/601) reported one or more children as under immunised, and 3.9% (23/601) reported that none of their children were immunised. ConclusionsThis survey demonstrates that data linkage for vaccine safety surveillance has substantial community support and that a system utilising opt-out consent or no consent was preferred to one using opt-in consent. These findings should inform public health policy and practice; data linkage should be established where feasible to address limitations in passive surveillance systems.

29th ESPID Annual Meeting in The Hague, the Netherlands

29th ESPID Annual Meeting in The Hague, the Netherlands

Nonclinical vaccine safety evaluation: advantages of continuous temperature monitoring using abdominally implanted data loggers

Fever has been reported as the most common adverse event after vaccination in infants and children. For this reason it is important that, prior to clinical testing of a new vaccine, change in body temperature following vaccination is tested carefully in nonclinical animal studies. Since both the timing and the height of the temperature peak after vaccination may differ from vaccine to vaccine, it is important that the time point for body temperature measurement should be chosen on a case-by-case basis with sufficient knowledge of the specific vaccine. In order to determine the best time point for rectal body temperature measurement after vaccination with a new vaccine candidate against N. meningitidis serogroup B, to be applied in a formal Good Laboratory Practice (GLP) toxicology study, miniature temperature data loggers were implanted into the peritoneal cavity of rabbits. The continuous body temperature monitoring appeared to give a complete picture of the entire body temperature kinetics after vaccination. The body temperature peaked at 4 h after vaccination, and this time point was subsequently applied in the toxicology study. Measured body temperature values at the selected time point of 4 h after vaccination were comparable in the continuous temperature setting and in the formal toxicology study, i.e. rectal temperature measurement at one time point. In the present study implanted temperature loggers were successfully used to define an adequate time point to be applied in determining rectal body temperature in a formal GLP toxicology study with a new vaccine candidate.

Vacina da varicela na infância

VARICELLA VACCINE IN CHILDREN Objectives: To review the available evidence for varicella vaccination in healthy children, analyzing its effectiveness and safe- ty. Data sources: MEDLINE database and evidence-based medicine websites. Methods: A search was conducted for guidelines, systematic reviews, meta-analyses and original studies, published between January 2005 and November 2009, in English, Portuguese and Spanish, using the MeSH terms chickenpox vaccine, infant, child preschool and child. The SORT (Strength of Recommendation Taxonomy) scale of the American Family Physician was applied to evaluate the level of evidence. Results: We found 14 studies that assessed vaccine effectiveness: 5 guidelines (2 with strength of recommendation A) 3 sys- tematic reviews (2 with evidence level 1), one meta-analysis (evidence level 1), a case-control study and 4 cohort studies. Stud- ies showed that the vaccine has an effectiveness of 70 to 90% in preventing all forms of varicella and 95 to 100% in prevent- ing moderate to severe disease, over a period not exceeding ten years. The two-dose regimen showed greater long-term effec- tiveness than the single dose regimen. Two studies evaluating vaccine safety concluded that the vaccine is safe and well toler- ated (one randomized controlled trial with evidence level 1). Conclusion: Varicella vaccine is effective and safe in healthy children (Strength of Recommendation A). However, its imple- mentation should be universal, to allow a high coverage rate, considering the possibility of a two-dose regimen.

The Food and Drug Administration's Post‐Licensure Rapid Immunization Safety Monitoring program: strengthening the federal vaccine safety enterprise

In 2009, the Department of Health and Human Services created the new Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, which used data from national health insurance plans and immunization registries to monitor the safety of the H1N1 influenza vaccine. PRISM has now been integrated into the FDA's Mini-Sentinel pilot program. It strengthens the federal vaccine safety enterprise in two important ways. First, PRISM monitors the largest US general population cohort designated for active surveillance of vaccine safety. Second, PRISM links data from health plans with data from state and city immunization registries, which were a crucial source of exposure data in the H1N1 vaccine evaluation. The Mini-Sentinel data that support PRISM are updated quarterly, and PRISM can conduct medical record review for validation of computerized data. The FDA has structured PRISM as a program that includes specific vaccine evaluations, development of an operational framework to guide the design of vaccine safety evaluations, and development of new statistical methods. A human papillomavirus vaccine, Gardasil, and two rotavirus vaccines, RotaTeq and Rotarix, have been chosen for surveillance in the current cycle because their evaluations would benefit most from PRISM's large cohort size. The PRISM program creates important opportunities by offering a robust, responsive new surveillance program with features complementary to existing systems. Methodological and logistical lessons can be shared among PRISM and other surveillance systems, offering potential synergies. FDA and PRISM will work to maximize the program's unique strengths and contributions to a unified federal vaccine safety enterprise.

A retrospective population‐based study on seizures related to childhood vaccination

Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort. We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006-2008 were analyzed retrospectively; available clinical information was reevaluated and classified by seizure type and epilepsy syndrome. In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients. Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety.

Statistical, Epidemiological, and Risk-Assessment Approaches to Evaluating Safety of Vaccines Throughout the Life Cycle at the Food and Drug Administration

The public health community faces increasing demands for improving vaccine safety while simultaneously increasing the number of vaccines available to prevent infectious diseases. The passage of the US Food and Drug Administration (FDA) Amendment Act of 2007 formalized the concept of life-cycle management of the risks and benefits of vaccines, from early clinical development through many years of use in large numbers of people. Harnessing scientific and technologic advances is necessary to improve vaccine-safety evaluation. The Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research is working to improve the FDA's ability to monitor vaccine safety by improving statistical, epidemiologic, and risk-assessment methods, gaining access to new sources of data, and exploring the use of genomics data. In this article we describe the current approaches, new resources, and future directions that the FDA is taking to improve the evaluation of vaccine safety.

In vivo molecular imaging for a nasal botulism vaccine in mice and nonhuman primates (53.8)

Abstract Nasal administration is an effective route for a needle-free vaccine. However, safety concerns were raised by the potential of nasally administered antigens to reach the central nervous system. We tested the real-time quantitative tracking of a nasal vaccine candidate for botulism, which is a recombinant nontoxic fragment of botulinus toxin A (BoHc/A), by using a newly established in vivo imaging method, [18F]-labeled BoHc/A-positron emission tomography (PET). This method provides results that are consistent with direct counting of [18F] radioactivity or the traditional [111In]-radiolabel method in dissected tissues of mice and non-human primates. In addition, no deposition of BoHc/A in the cerebrum and olfactory bulb was found after nasal administration of [18F]-BoHc/A in mice and non-human primates. We also established a real-time quantitative profile of elimination of this nasal vaccine candidate and demonstrated that it induces highly protective immunity against botulism in non-human primates. These results demonstrate a new way to use in vivo imaging for safety evaluation of nasal vaccines.

Fever following administration of two inactivated influenza vaccines—A survey of parents of New Zealand infants and children 5 years of age and under

Due to a dramatic increase in reported febrile convulsions in Western Australia following a routine pediatric influenza vaccination programme we evaluated parental recall of fever in their child following 2010 trivalent influenza vaccine manufactured by either Sanofi Pasteur (Vaxigrip ®) or CSL Biotherapies (Fluvax ®) to determine if the rates of febrile events in infants and children 5 years and under following administration of either Vaxigrip ® or Fluvax ® were significantly different. Method A convenience sample of New Zealand General practices who had received stocks of the vaccines of interest consecutively contacted parents of infants and children under 5 years of age who received at least one dose of 2010 influenza vaccine. A brief questionnaire was administered with the main outcome parental recall of fever within 24 h of vaccination. Results Response rate was 99%. There were 327 parents of children aged 6 months to 5 years attending one of 23 primary care practices who had received a dose of either the Vaxigrip ® or Fluvax ® vaccine between 4th March and 28th June 2010 surveyed. A total of 422 doses were given of which 267 were Vaxigrip ®, 133 were Fluvax ® and 22 another vaccine. Fever occurred significantly more frequently within 24 h following administration of Fluvax ® compared with Vaxigrip ® RR 4.33 (2.44–7.70). When fevers were measured they were, on average, higher in the Fluvax ® vaccines (38 °C compared with 39 °C). Additionally, recipients were more likely to seek medical advice for fever following Fluvax ® RR 23.11 (2.96–180.12). Conclusions There is considerable variation in reactogenicity between two 2010 seasonal vaccines in infants and young children. Vaxigrip ® is significantly less reactogenic when compared to Fluvax ® in this population in which Fluvax ® is associated with unacceptably high rates of febrile reactions. There has been insufficient safety evaluation of seasonal influenza vaccine safety in this population.

C-B5-02: H1N1 Vaccine Safety Monitoring in the Vaccine Safety Datalink Project: New Challenges and Useful Lessons

Background and Aims: The worldwide introduction of influenza A (H1N1) vaccines in fall 2009 has raised widespread public questions about the safety of these new vaccines. The Vaccine Safety Datalink Project, a collaboration among CDC and eight health care systems in the HMORN, began accelerated monitoring of this vaccine’s safety in early fall 2009. Methods: The VSD Project conducts near real-time monitoring of potential adverse events following vaccination for all new vaccines. Each week, each site updates dynamic data files, and the coordinating center analyzes all data cumulatively. Repeated analysis of the same data requires adjustment for multiple testing. To address this issue, VSD uses sequential statistical methods. Evaluation of H1N1 vaccine safety poses special challenges, including confounding by indication, seasonality, and new priority groups including pregnant women. We are using several analytic methods, including: Self-controlled case-series, which compares exposed vs. unexposed time windows within the same individual; Poisson, which compares the outcomes during the current season with expected rates based on historical data for seasonal influenza vaccine; and Difference-in-difference, which compares the relative risk in exposed vs. unexposed time windows for H1N1 vaccine during the current season with the relative risk for seasonal influenza vaccine during cumulative prior seasons. Results: Pre-specified outcomes of interest include: Guillain-Barre syndrome, neuropathies, seizures, encephalitis, Bell’s palsy, ataxia, anaphylaxis, spontaneous abortion, pre-eclampsia, stroke, myocarditis and wheezing. Historical rates of these outcomes were calculated for time windows after seasonal influenza vaccination in prior seasons (2000/01–2008/09). The sequential analysis methods above will be used, and relative and absolute risks will be estimated for each outcome. For outcomes found associated with vaccination in preliminary analyses, additional evaluation will be conducted using temporal scan analyses, logistic regression, and when appropriate, medical record review.

RotaTeq: Progress toward Developing World Access

Phase III studies of an oral, live, pentavalent, human-bovine reassortant rotavirus vaccine (RotaTeq; Merck) in developed countries have demonstrated that it is well tolerated with regard to intussusception and other adverse events and is efficacious in preventing rotavirus gastroenteritis and associated healthcare encounters. However, it cannot be assumed that rotavirus vaccines will be equally efficacious in infants and young children in the developing world. Differences in host populations, associated health conditions, and the epidemiology of rotavirus disease could affect vaccine performance. Concern about the potential for differences in efficacy stems from studies of previous candidate rotavirus vaccines, including bovine and rhesus rotaviruses, which showed no or variable efficacy in developing regions. Given this history, the World Health Organization (WHO) recommended that the efficacy of "new" rotavirus vaccines should be demonstrated in diverse geographic areas, including developing countries, before widespread implementation. Successful implementation of any rotavirus vaccine in the developing world requires additional clinical research and sharing of early introduction experiences. We discuss efforts to bring RotaTeq vaccine to the developing world. Critical steps to achieve this goal include the clinical evaluation of vaccine safety and efficacy in a multisite trial in Asia and Africa, evaluation of concomitant use with other pediatric vaccines routinely used, and vaccine assessment in special populations (premature, human immunodeficiency virus-infected, and malnourished infants). Completion of WHO prequalification of RotaTeq and affordability are also key requirements to routine vaccine introduction. The RotaTeq Partnership with the Nicaraguan Ministry of Health provides an example of the successful introduction of this vaccine into a developing world country.

Sequential generalized likelihood ratio tests for vaccine safety evaluation

The evaluation of vaccine safety involves pre-clinical animal studies, pre-licensure randomized clinical trials, and post-licensure safety studies. Sequential design and analysis are of particular interest because they allow early termination of the trial or quick detection that the vaccine exceeds a prescribed bound on the adverse event rate. After a review of the recent developments in this area, we propose a new class of sequential generalized likelihood ratio tests for evaluating adverse event rates in two-armed pre-licensure clinical trials and single-armed post-licensure studies. The proposed approach is illustrated using data from the Rotavirus Efficacy and Safety Trial. Simulation studies of the performance of the proposed approach and other methods are also given.

High-throughput automated image analysis of neuroinflammation and neurodegeneration enables quantitative assessment of virus neurovirulence

Historically, the safety of live attenuated vaccine candidates against neurotropic viruses was assessed by semi-quantitative analysis of virus-induced histopathology in the central nervous system of monkeys. We have developed a high-throughput automated image analysis (AIA) for the quantitative assessment of virus-induced neuroinflammation and neurodegeneration. Evaluation of the results generated by AIA showed that quantitative estimates of lymphocytic infiltration, microglial activation, and neurodegeneration strongly and significantly correlated with results of traditional histopathological scoring. In addition, we show that AIA is a targeted, objective, accurate, and time-efficient approach that provides reliable differentiation of virus neurovirulence. As such, it may become a useful tool in establishing consistent analytical standards across research and development laboratories and regulatory agencies, and may improve the safety evaluation of live virus vaccines. The implementation of this high-throughput AIA will markedly advance many fields of research including virology, neuroinflammation, neuroscience, and vaccinology.