The need for Modeling and Simulation in Vaccine Development – Certara

Within an , I outlined a task to build up a Modeling & Simulation (M&S) timing model – being an alternate method of dedicated studies – to look for the ideal time to vaccinate women that are pregnant. This model could then be further used to predict infant antibody (Ab) levels at birth and eventually be utilized for an invaluable quantitative method of vaccine development.

Fit to Maternal Antibody Data

To evaluate how good our model will match the present trial study data, the timing model simulations were when compared to maternal vaccination data acquired from studies conducted through the Maternal Immunization Working Group within the Cdc (CDC) in Nigeria, Mali, and Nepal. The model was trained while using Nigeria and Mali trial datasets, and also the Nepal data was utilized being an exterior validation step.

The outcomes from the simulation shown the model adequately captures the baseline, an upswing, and nov maternal titer levels. The model fit data was symbolized inside a box plot according to quantity of visits, plotting Time after Vaccination in days (x-axis) versus Antibody Titer (y-axis). Resolution of antibody titers would be a complicated process – the assay studies were conducted in every study center lab versus just one central lab facility. The antibodies are assessed with an initial dilution from the sample – that is different across trials – after which serially diluted before the sample doesn’t block an indication within an in vitro assay. The reported dilution values represent digital or purchased categorical data.

Box Plot to show Model Fit to Maternal Influenza Antibody data

The median from the information is proven through the lines of horizontal type in each one of the boxes and also the 5th and 95th percentile from the data seems because the extent from the box. The model fits are proven because the median of conjecture (the solid blue line) and variation/variability (blue envelope). The model was proven to suit towards the study data as ideally the median and also the conjecture should fall into line using the data median and also the variation/variability within the envelope coincide using the edges from the box plots as shown within the plot.

We gain understanding from all of these simulations – we all know that it requires 20 days to recruit plasma cells to begin producing antibodies. With simulations, we discover that more than a 1 year period, 85% from the titer is created by lengthy-resided plasma cell population and short-resided plasma cells possess a three day half-existence. So, a lot of antibodies are created immediately which, more than a time period of days, may well be a essential cell population.

We’re also performing a covariate search to assist comprehend the factors adding towards the heterogeneity observed in the information.

Time for you to Maximal Influenza Antibody Production

The model seemed to be accustomed to perform simulations to calculate time span of antibody production after vaccination: a clear, crisp rise occurs roughly 20 days after vaccination, peaks around 8 days, then gradually declines following the peak because of antibody turnover and plasma cell population turnover.

Another simulation was performed to check towards the Nepal data set, which contained a significantly sparser sampling schedule and fewer subject data versus the Nigeria and Mali datasets. Within this simulation, i was able predict study results by searching in the medians 13 days publish-vaccination thus creating an essential validation step with this project.

While using Timing Model to Simulate Optimal Timing of Other Vaccines

To determine how our model simulation results on predicting maternal influenza antibody when compared with existing studies for other vaccines, we compared the influenza simulation leads to Tdap (Tetanus, Diphtheria, Pertussis) studies. The Consultant Committee on Immunization Practices (ACIP) recommends the Tdap vaccine be administered to women that are pregnant between 27 – 36 days of pregnancy. A completely independent Tdap prospective study conducted by Eberhardt and colleagues on 335 women that are pregnant immunized within the second or third trimester figured that resistant to the ACIP recommendation, the first second trimester created a greater infant antibody titer.1 Our simulation, on predicted maternal influenza antibody titers, carefully matched the newborn Tdap titer optimum as reported by Eberhardt showing alignment from the influenza vaccine within the Tdap titer kinetics.

It is really an exciting observation, which raises an intriguing question. Both of these vaccines make use of the same humoral immunity system to create these antibodies. Because we acquired similar kinetic patterns with two different vaccines, are these kinetics sign of many vaccines? These bits of information claim that more precise tips about vaccine administration are possible, i.e. six to eight days just before delivery.

Predicting Infant Influenza Antibodies at Birth

Our next thing is defined the effectiveness of the model was to look for the consistency from the infant: maternal antibody ratio at birth.

Predicted versus Observed Infant Influenza Antibodies at Birth

Our findings established that the newborn antibody titer highly will mean you get the maternal ratio at birth. Most significantly, an evaluation of predicted versus observed infant birth titers shown relatively good alignment indicating the maternal antibody level may be used to predict the newborn antibody level at delivery.

Other facets of the model we examined would predict infant antibody levels regarding time. For instance, bodyweight, gestational age, and postnatal age are known factors that impact antibody clearance in youngsters.

Searching towards the Future – Linking Infant Influenza Antibody Titer Level to Protection

Our future work will concentrate on while using model to find out how infant antibody levels match protection against influenza. We still collaborate using the Maternal Influenza Immunization Data Analysis Working Group to locate the relationship between titer level and protection. Once the work is finished, we’ll established a quantitative modeling approach to look for the sequence of occasions – from vaccination within the mother to quantitative assessment of protection in infants. It’s achievable to operate simulations to derive permutations of possible occasions for vaccinating moms, obtain protection curves for that infants, and eventually target the response curve of protection in accordance with the mother’s vaccination time.


The need for Modeling and Simulation in Vaccine Development - Certara vaccines, we compared
  1. Eberhardt,S., Blanchard-Rohner,G., Lemaître, B., et al. (2016). Maternal Immunization Earlier during pregnancy Maximizes Antibody Transfer and Expected Infant Seropositivity Against Pertussis. Clin. Infect. Dis., 62(7), 829-836.

To find out more about how this timing model may be used to optimize maternal antibody levels and predict infant antibodies at birth, please watch this web seminar I conducted about this project.


Common Myths about PBPK Modeling and Simulation- Busted!