Q1 Rotavirus is a major cause of severe gastroenteritis among young children. Each year, rotavirus causes >500,000 deaths worldwide among infants and very young children, with 90% of these deaths occurring in Africa and Asia. In low income countries, it is a major cause of under-5 year old mortality, accounting for up to 20% of all childhood deaths in countries with a high diarrhoeal disease burden. Infections in the first 6 months of life are associated with severe symptoms and therefore good vaccination coverage early in life is important. Rotavirus infection is primarily spread via the faecal-oral route. Recently two orally-administered, live, attenuated vaccines against rotavirus infection have been licensed and are now being implemented into routine immunization programmes in several countries. The 2 vaccines differ by the number of doses that are recommended to be given; the first vaccine should be administered in 2 doses and the second vaccine should be administered in 3 doses. Two large scale clinical trials have demonstrated that the vaccine is safe and highly efficacious. The first trial was carried out in several countries across Latin America. This trial used the 2 dose vaccine. The second trial was undertaken in several countries in Europe and the USA, and used the 3 dose vaccine. Below is a summary of results for each trial. Table 1: Hospitalisation cases of severe Rotavirus for the 2 Randomised Control Trials (RCT) RCT Latin America 2 doses of vaccine Europe & USA 3 doses of vaccine Total number in vaccine group Number of cases in vaccine group Total number in control group Number of cases in control group 7,205 22 7,081 127 28,646 6 28,488 144 a. Explain the meaning of vaccine efficacy and calculate the VE for each study (please show all your workings) (25 marks) the standard measure of how well a vaccine works, the % reduction in incidence in vaccinated individuals attributable to vaccination (5 marks) 10 marks for each VE calculated Latin America study: 1- (22/7205)/(127/7081)1-0.003053/0.0179= 0.17 1-0.17 = 82.98%
Europe & USA 1-(6/28646)/(144/28488) 1-0.00020945/0.0050547 = 0.0414 1-0.0414 = 95.9% b. State four reasons for being cautious when comparing the results from these vaccine trials. (20 marks) 5 marks for each valid reason up to maximum 20 marks - Inclusion criteria, age at vaccination, may differ, so the results may not be comparable - The duration of follow-up is not stated, may differ, this matters if efficacy may wane - The timing of the doses is not stated, infections in the first 6 months are important, different regimens may give different protection at early age - Need more information on how both studies were carried out were they blinded, how the randomisation was carried out, and the case definition and diagnostic criteria - Limited information provided on the results e.g. no confidence intervals, so difficult to compare results - Different regions the observed differences may reflect differences between the vaccines, or differences in site specific factors that affect vaccine efficacy (e.g. age distribution of cases) You are responsible for selecting a rotavirus vaccine for your country as currently no vaccine for rotavirus is being used. Your country is a low income country in sub-saharan Africa with very high under-5 mortality. Diarrhoea is a leading cause of child mortality and morbidity. d. State four additional pieces of information you would want in order to make a more informed decision about which rotavirus vaccine to introduce in your country (20 marks) 5 marks for each valid point up to maximum 20 points: - incidence of vaccine-related serious adverse events - age specific rotavirus incidence, in relation to the timings of doses in the 2-dose and 3-dose schedule - confidence intervals for VE for each vaccine to confirm if there is a difference in efficacy - efficacy after 2 doses for the 3-dose vaccine - effect of co-administration with other EPI vaccines on responses to both vaccines - vaccine uptake data in your country to determine whether good coverage of 3 doses could be achieved - a cost effectiveness analysis - logistical requirements such as cold chain
- the VE for each vaccine in your country (important because of variable efficacy of live oral vaccines) - duration of protection for both vaccines - evidence of herd effect You have limited funds for health care and hospitals resources for proper management of severe diarrhoea are scarce in many regions in your country. The cost of the vaccine is $10 (USD) per dose (regardless of which vaccine is used). The current recommendation from the vaccine developers is to administer the first dose of rotavirus vaccine between 6 and 12 weeks of age. Previous studies have shown that an older vaccine for rotavirus had an increased risk of serious adverse events (risk of bowel obstruction estimated to be 1 case per 10,000) when the first dose was administered AFTER 12 weeks of age. Based on this risk, the vaccine was withdrawn from public use. e. Based on the information provided in this question (including your VE estimates), which vaccine would you select for introduction into your country s immunization programme? Justify your answer (15 marks) Either vaccine can be chosen as long as appropriate justification is given: 3 dose vaccine: - higher VE for 3 doses versus 2 doses and thus preventing more deaths - can be incorporated into existing EPI schedule - appropriate choice if good coverage of 3 doses could be achieved - low risk of doses being administered after 12 weeks 2 dose vaccine: - 2 dose is cheaper than 3 doses - easier for a better coverage of 2 doses versus 3 doses - the 2-dose schedule reduces the potential for late administration of doses beyond 12 weeks. - less risk of adverse events for 2 doses than 3 doses f. Briefly describe what studies you would conduct after the vaccine was introduced in order to monitor its impact (20 marks) 5 marks for each of the following: - Disease surveillance to monitor impact - Case control study to measure vaccine efficacy - Adverse event surveillance - Vaccination coverage surveys to measure coverage and timing of doses
Rate per 100 000 population Q2 During the first wave of the H1N1 influenza pandemic from April to September 2009 in England it is estimated that 320,000 people reported with clinical illness. However, this varied considerably by age group and region. Outbreaks in schools occurred, following the introduction of infection by school-age children who had acquired infection through travel or through contact with other cases in the household or elsewhere. Figure 1: Estimated rate, per 100,000 population of clinical cases of pandemic H1N1 2009 by age group and strategic health authority, England to September 2009 (East Midlands (EM), East of England (EE), London (LN), North East (NE), North West (NW), South Central (SC), South East Coast (SE), South West (SW), West Midlands (WM), Yorks & Humber (YH) 2000 1500 1000 500 0 Age Group <1 yr 1-4 yr 5-14 yr 15-24 yr 25-44 yr 45-64 65+ a. Describe the age pattern of infection (5) People aged 5-24 years were more likely (2-3 times incidence) to become infected than older adults (3 marks). Low incidence in >65yrs (2 marks). b. Give two reasons why in contrast to seasonal influenza, people 65 years and older might be least affected. (10) This age pattern likely reflects past exposures to other strains of H1N1 and some level of cross-protecting antibodies among older age groups. (5) Less contact with other people, many of the outbreaks were in schools and workplaces (5)
Give one reason that might explain the heterogeneous geographical distribution (5) 5 marks for any valid answer for example: Outbreaks in some parts of the country and not others (5) Susceptibility of host population (eg more young people in London) (5) International linkage of populations (early introductions due to travel) (5) c. Why does seasonal influenza tend to peak in the temperate winter season? (5) The incidence of droplet- transmitted diseases such as influenza tends to peak in the temperate winter season for a number of reasons. In temperate climates, there tends to be more crowding and less ventilation in winter (2 marks). This leads to increased contact, re-circulation of air and dry nasal mucosa, providing a better environment for transmission (3 marks). The size and relative impact of influenza epidemics and pandemics depend upon several factors including natural or vaccine-induced levels of protective immunity in the population, strain virulence and the extent of antigenic variation of new viruses. This H1N1 pandemic strain is not thought to be as virulent as previous pandemic strains. Most cases appear to have experienced a typical influenza-like illness. d. What does virulence mean? (5) Virulence is the amount of pathogenicity that an infectious agent causes, that is, the severity of the disease that may result from an infection. Intensive epidemiological and laboratory investigation of the first few hundred cases and their household contacts were used to estimate key transmission parameters for the pandemic virus. The secondary attack rate was 7%; however, the rate was approximately four times higher in children (<16 years) than adults. Early findings from the pandemic estimated that the basic reproductive number (Ro) ranged from 1.4 to 1.6. Asymptomatic infection is a well-recognised feature of seasonal influenza. However, the proportion of those infected with the pandemic (H1N1) virus that had a mild illness or are asymptomatic has not been well-characterised. e. Explain what a secondary attack rate of 7% means? (5) SAR of 7% means that 7 out of 100 susceptible persons exposed to a primary case developed the disease as a consequence of contact with this primary case(5) f. What information do you need to calculate the secondary attack rate (SAR)? (15) Exact time of onset of each case (serial interval between cases) (5) Number of susceptible exposed to the primary case (5) Estimate of the maximum infectious period and the minimum and maximum incubation periods of the disease (5) Comment [E1]: This should be the minimum and maximum serial interval I think Andy
g. State three criteria that should be considered when deciding which clinical manifestation to use to identify the exact time of onset of each case when calculating the SAR? (15) Constancy of presence (asymptomatic cases, mild illness) Extraneous variability ie variability not attributable to the biology of the disease eg variability in memory, reporting, observation Stability in the cycle of the disease (no clear manifestation) h. If you count as susceptible some individuals who are actually immune to the disease, what effect would this have on the calculated SAR? Briefly explain your answer. (5) The calculated SAR would be an underestimate of the true transmission probability (2 marks) as including those who are not actually susceptible to the disease would artificially raise the denominator (3 marks). i. If a large number of secondary cases were asymptomatic what effect would this have on the calculated SAR? Briefly explain your answer. (5) The calculated SAR would be an underestimate (2 marks) as asymptomatic cases not included in the numerator (3 marks). j. What does a basic reproductive number, Ro of 1.4 mean? (5 marks) Each single primary case is expected to produce 1.4 secondary cases in a totally susceptible population (average number of secondary cases arising from a primary case in a susceptible population).(5) k. Define net reproduction number, R ( 5 marks) R: The average number of secondary infective cases produced by each primary case in a population where not all the individuals are susceptible. l. Explain in words the relationship between the Ro and R (5 marks) R is the product of Ro times the proportion of the population that are susceptible (x). m. A report on the H1N1 epidemic stated that if a second wave of infection were to occur, the basic reproduction number would be expected to be lower than in the first epidemic. State two reasons why the basic reproduction rate would be expected to be lower in the second outbreak. (You do not need to do a calculation) (10 marks) any two of the following: Public health interventions eg closure of schools, that reduce the contact rate (5 marks) Vaccination (5 marks) Behaviour change through public education (5 marks)
The virus could mutate and become more or less transmissible or persist more or less time in the host (5 marks)