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Journal Club summaries - 2012

Evolution of immune response against Neisseria meningitidis B:14:P1.7,16 before and after the outer membrane vesicle vaccine MenBvac

Caron F, Delbos V, Houivet E, et al. 
Vaccine 2012;30(34):5059-62
Link to abstract

A universal multiple component vaccine targeting meningococcal serogroup B (MenB) disease was recently submitted for regulatory review in Europe, and similar submissions are anticipated in Australia in the near future. It is therefore timely to bring MenB vaccines to the forefront of discussions, and to review the lessons learnt from previous use of vaccines for the control of MenB disease – albeit vaccines with substantially different components and antigenic targets to those under regulatory review. 

Previous control of MenB disease in outbreak situations has been based on tailor-made vaccines effective only against the targeted clone. A meningococcal B:14:P1.7,16 outbreak in Normandy (France) was recently controlled using MenBvac, an outer membrane vesicle vaccine previously designed against the B:15:P1.7,16 strain. The further emergence of a new B:14:P1.7,16 outbreak in another district in Normandy led to the exploration of immunity against B:14:P1.7,16 before and after a MenBvac campaign; using a 2+1 (day 0, week 6, month 8) schedule. 

In this study, children (aged 1–5 years) were sampled before, during and up to 1 year after vaccination. Serum bactericidal activity against B:14:P1.7,16 was titrated using human complement (hSBA) and immune response was defined by hSBA titre of 4 or higher as a surrogate for protection. The authors report an hSBA titre of 4 or higher in 10.8% of participants before vaccination, raised to 84.1% 6 weeks after the completion of the schedule, but declined to 39.7% 1 year later. This is lower than the targeted 60% level and suggests only short-term persistence of response against B:14:P1.7,16 using a 2+1 schedule. The findings were limited by overall poor response rates and poor availability of blood samples from the participants at each of the chosen time points. 

Nevertheless, this study highlights a number of important factors that should be taken into account in the review of future vaccine candidates: (1) relatively high rates of natural immunity against the targeted clone diminishing the percentage of vaccine responders; (2) challenges in the interpretation of assays using human sources of complement, hindering comparisons across studies; (3) insufficient long-term immunity despite substantial boosting effect; and (4) highly variable immunity against the targeted MenB clone observed across populations. We hope that the candidate universal MenB vaccines can overcome the limitations observed with the past use of MenBvac. 

Presented by Brett Archer, Research Officer, NCIRS

Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy

Pasternak B, Svanström H, Mølgaard-Nielsen D, et al.
JAMA 2012;308(2):165-74
Link to abstract

During the 2009 influenza A(H1N1) pandemic, pregnant women were among those targeted for vaccination. Assessment of fetal safety following maternal vaccination has been limited to pharmacovigilance and descriptive cohort studies.

The aim of this study was to investigate whether in utero exposure to AS03-adjuvanted influenza A(H1N1)pdm09 vaccine is associated with an increased risk of major birth defects if exposed during the first trimester of pregnancy, or preterm birth or fetal growth restriction when exposed at any time during pregnancy.

This was a registry-based cohort study conducted in Denmark. The birth cohort were identified through the Danish Medical Birth Register, and linkage to other databases facilitated by unique personal identification numbers assigned to all Danish residents.

Multiple births, missing gestational age or birth weight, and infants with congenital abnormalities with known causes were excluded, as were mothers who were vaccinated prior to pregnancy. Potential confounders considered included maternal age; place of birth; urbanisation of place of residence; parity; smoking status; pre-pregnancy body mass index; history of spontaneous abortion, birth defects, or small for gestational age deliveries; and maternal prescription drug use.

Data was analysed using a propensity score-matched analysis, and an unmatched cohort analysis. The data was analysed in two groups: first trimester exposure, and second or third trimester exposure.

The unmatched cohort analysis showed that vaccination during the first trimester had a higher prevalence of major birth defect (POR 2.26; 95% CI: 1.40–3.66) and preterm birth (POR 2.08; 95% CI: 1.45–2.99), while all other outcomes were not significantly different. There was no difference in outcomes demonstrated in the unmatched analysis for second and third trimester exposure.

Propensity score-matched analysis showed no significant differences in outcomes for exposed and unexposed groups for any exposure timeframe.

The authors discuss that in Denmark women who had a pre-existing condition associated with an increased risk of severe influenza infection, such as cardiovascular disease, were recommended to have the vaccine in trimester one, while all other pregnant women were recommended to receive the vaccine in trimester two. The differences between these groups may explain the increased risk seen in the unmatched analysis, which was not seen in the propensity score-matched analysis.

The authors conclude that this study found no significant association between AS03-adjuvanted influenza A(H1N1)pdm09 vaccine administration during pregnancy and an increased risk of major birth defects, preterm birth or fetal growth restriction. They caution that while the results provide “robust evidence” for outcomes associated with second or third trimester exposure to the vaccine, the results for first trimester exposure should be treated as preliminary and in need of confirmation.

Presented by Kerrie Wiley, PhD student – Social Research, NCIRS

Safety and immunogenicity of live attenuated and inactivated influenza vaccines in children with cancer

Carr S, Allison KJ, Van De Velde LA, et al.
Journal of Infectious Diseases 2011;204(10):1475-82
Link to abstract

Children with cancer are considered to have a higher risk of acquiring influenza infection and complications (J Pediatr 1989;115:33-9; J Clin Pathol 1991;44:297-9). A review by Gross (Rev Infect Dis 1985;7:613-8) reported trivalent inactivated vaccine (TIV) recipients with cancer developed lower antibody titres than healthy control subjects. Also, data are limited on live, attenuated influenza vaccine (LAIV) use in immunocompromised patients. The study by Carr et al. compared the safety and immunogenicity of LAIV vs TIV in children with cancer. 

The study included children and young adults with cancer (aged 2–21 years) who were mild to moderately immunocompromised, had stable disease or were in remission, receiving or having received chemotherapy and/or radiotherapy within the past 3 months. Exclusion criteria were 1) absolute neutrophil count lower than 500 cells/mm3 within prior 72 hours; 2) receipt of current year influenza vaccine; 3) receipt of immunoglobulin within 90 days; 4) close contact with another severely immunocompromised patient; or 5) receipt of haematopoietic stem cell transplant. Randomisation was performed using stratification of age and influenza vaccination history at a ratio of 1:1. For children aged less than 9 years with a history of less than 2 prior influenza vaccinations, 2 doses of vaccine were given 28–42 days apart. Other subjects received 1 dose only. The study vaccines were LAIV (FluMist, MedImmune; intranasal; 0.2 mL) and TIV (Fluzone, Aventis Pasteur; intramuscular; 0.25 mL for children aged less than 3 years, 0.5 mL for older children) for the 2008–2009 northern hemisphere season. A diary card was used for the 28 days post vaccination. All participants were seen in clinic 28–42 days after each vaccination. Data on serious adverse events were collected up to 180 days post vaccination. If an influenza-like illness occurred within 28 days after vaccination, nasal swabs were collected and tested for influenza. Blood samples were collected before and 28–42 days after vaccination. The seroprotection rate was assessed by haemagglutination inhibition (HAI) titre (1:40). The seroconversion rate was defined as the percentage of vaccinees with a 4 or greater fold increase in HAI titres from a seropositive prevaccination titre (10 or higher), or the percentage of seronegative vaccinees with a rise from less than 10 to 40 or higher. 

A total of 56 subjects were randomised during 14 October–31 December 2008. The safety profile was similar in both (LAIV and TIV) groups after 10–28 days. HAI immunogenicity data after completion of vaccination with LAIV or TIV showed that TIV was significantly more immunogenic for flu A but no differences were noted for flu B. 

Microneutralisation titres were generally higher for all antigens than were HAI titres. After control for vaccine type, younger subjects were more likely to seroconvert to H1, compared with older subjects (p=0.05). Older subjects were more likely to have seroprotection against H3 (p=0.04). When age was dichotomised (less than 9 years vs 9 years and older), the higher rate of seroconversion to H1 in younger subjects was no longer observed. Based on the authors’ findings, TIV should be chosen to prevent influenza in high-risk immunocompromised individuals. More studies are required to better address the protection of LAIV in immunocompromised children and to identify the difference in vaccine response based on the number of circulating lymphocytes/neutrophils. Other options can be considered as well, such as using higher antigen doses and adjuvanted influenza vaccine.

Presented by Kevin Jiehui Yin, Research Officer/PhD Candidate, NCIRS

Attitudes and practices of obstetrician-gynecologists regarding influenza vaccination in pregnancy

Kissin DM, Power ML, Kahn EB, et al. 
Obstetrics and Gynecology 2011;118(5):1074-80
Link to abstract

Pregnant women are at increased risk for influenza-related morbidity, adverse pregnancy outcomes, and mortality, especially during pandemics. Influenza vaccination during pregnancy is the most effective way to prevent influenza infection among pregnant women and their infants younger than 6 months of age. Vaccination coverage among pregnant women in the United States has been historically low, around 15% during non-pandemic years.

The aim of this study was to assess knowledge, attitudes and practices of obstetrician–gynecologists regarding vaccination of pregnant women during the 2009 H1N1 pandemic in the United States and assess the predictors of routinely offering influenza vaccination.

From February to July 2010, a random sample of American College of Obstetricians and Gynecologists members involved in obstetric care completed a self-administered mail survey. Of 873 eligible participants, 77.6% reported routinely offering the seasonal influenza vaccine and 85.6% routinely offered the 2009 H1N1 influenza vaccination to their pregnant patients during the 2009–2010 influenza season. Seasonal and 2009 H1N1 influenza vaccination during the first trimester was not recommended by 10.6% and 9.6% of obstetrician–gynecologists, respectively.

Reported reasons for not offering vaccination included inadequate reimbursement, storage limitations, or belief that vaccine should be administered by another provider. Significant predictors of routinely offering 2009 H1N1 influenza vaccine included: considering primary care and preventive medicine a very important part of practice; observing serious conditions attributed to influenza-like illness; personally receiving 2009 H1N1 influenza vaccination; and practicing in a multispecialty group. Physicians in solo practice were less likely to routinely offer influenza vaccine.

Improving coverage rates during pregnancy is one of the main public health goals during both influenza pandemics and non-pandemic seasons. For many women, obstetrician–gynecologists are the only providers of health care during pregnancy. Policy improvements to allow more reliable reimbursement for vaccine providers, especially those in solo practice, might be beneficial. Obstetrician–gynecologists played a crucial role in increasing national influenza vaccination coverage among pregnant women during the 2009 H1N1 pandemic and need to sustain their role as vaccinators during coming influenza seasons.

Presented by Brynley Hull, Epidemiologist, NCIRS

AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland

Nohynek H, Jokinen J, Partinen M, et al.
PLoS ONE 2012;7(3):e33536
Link to abstract

This article describes the findings of a retrospective cohort study evaluating the observed safety signal suggesting association between Pandemrix vaccination and abrupt manifestation of narcolepsy in childhood and adolescence (4–19 years of age). A sudden increase in childhood narcolepsy was observed in Finland soon after the pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. Narcolepsy is a chronic sleep disorder causing excessive daytime sleepiness and cataplexy with a strong genetic predisposition which has never before been reported in association with vaccination. 

The ASO3 Pandemrix vaccine was introduced nationwide in Finland from October 2009; no other pandemic vaccines were available in the country. Vaccination coverage across Finland during this period was 52% with 75% coverage in the 4–19 years old cohort. Compared to the baseline incidence of 0.79/100,000 person-years, the incidence of narcolepsy in the vaccinated group was 9/100,000 person years. A 12.7-fold risk of narcolepsy was found in the 4–19-year-old individuals within approximately 8 months after the Pandemrix vaccination which translated into a vaccine attributable risk of 1:16,000. The findings were also supported by the results from Sweden where a cohort study covering the entire population reported an almost 7-fold incidence of narcolepsy with cataplexy in children vaccinated with Pandemrix compared to unvaccinated children in the same age group. Data from France, Norway and Ireland also indicate a higher than expected number of cases in children and adolescents after Pandemrix vaccination. Because of a lack of signal in the UK and Canada, a multifactorial nature of the phenomenon has also been suggested. 

This study was based on comprehensive data and covers the entire population of Finland. The results indicate a strong association between the Pandemrix vaccination and narcolepsy. The authors go on to say that several infectious, environmental, social or psychological factors could modify the strength of the association seen in this study but none could completely undo an association of this magnitude. Their findings have raised concerns about lipid containing adjuvants and calls for further research of their association with adverse effects such as autoimmunity.

Presented by Latika Naidu, Public Health Registrar, NCIRS

Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b 

Sun Y, Christensen J, Hviid A, et al.
JAMA 2012;307(8):823-31
Link to abstract

A whole-of-country cohort study was undertaken in Denmark to assess the relationship of febrile seizures (FS) in infancy with this multi-component vaccine containing pertussis toxoid, and also the risk of epilepsy in vaccinated children. The birth cohort consisted of nearly 400,000 children born between 2003 and 2008. Vaccination records were obtained from the national health insurance registry, and hospital presentations (inpatient and outpatient) from the national hospital register. Unique identifiers allowed for linkage with other statistical databases and measurement and control of other perinatal, maternal and socioeconomic factors. The analysis was by the Cox proportional hazards model, with the ‘exposed’ post-vaccination risk period defined as day 0 (the day of vaccination) up to 7 days after. Secondary analyses further defined this period as days 0, day 1–3 and 4–7. A self-controlled case series analysis was also conducted.

There was an overall lower incidence of epilepsy in vaccinated compared with unvaccinated children (HR 0.63, 95% CI: 0.50–0.79 up to age 15 months; HR 1.01, 95% CI: 0.66–1.56 for age 16 months–7 years). There was little evidence of an overall increase in risk of febrile seizure in the week after vaccination, although as high as a 3-fold increase after dose 1 cannot be excluded. There was also a clustering of FS events on the day of vaccination, adding weight to the existence of a true small increase in risk. The study limitations included potential misclassification of FS and epilepsy, differential ascertainment of events for vaccinated versus unvaccinated children, residual confounding (e.g. a healthy vaccinee effect), imprecision of risk estimates on sub-analyses due to small case numbers, and bias from multiple comparisons. Overall, the most likely net direction of bias is toward underestimation of the risk associated with vaccination.

Extrapolating from the data presented: at most (i.e. taking the upper boundary of the 95% CI), vaccination might account for an additional approximately 70 FS per 100,000 vaccinees compared to a background risk of FS in the population of approximately 2,000 per 100,000 (i.e. <2% of all FS). The most likely estimate is of <5 additional FS per 100,000 doses (i.e. <0.01 of all FS) attributable to vaccination. 

Presented by Tom Snelling, Senior Clinical Fellow, NCIRS

Recurrent apnoea post immunisation: informing re-immunisation policy

Clifford V, Crawford NW, Royle J, et al. 
Vaccine. 2011;29(34):5681-7
Link to abstract

Preterm infants are recommended to receive their immunisations according to chronological age. However, it is known that some preterm infants may have apnoea as an adverse event following immunisation (AEFI). There are relatively few studies which examine the risk of recurrent apnoea with subsequent immunisations in infants who experience apnoea AEFI. 

This study sought to describe rates of recurrence of apnoea AEFI in preterm and term infants who experienced apnoea AEFI following their scheduled 2- and 4-month immunisations. The study also sought to describe the clinical features of recurrent apnoea, and to look for potential risk factors for recurrence of apnoea AEFI with subsequent immunisations.

All infants who were reported to the Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) system as having experienced apnoea AEFI between 1 May 2007 and 30 April 2010 were included in the study. SAEFVIC is a passive surveillance system used to monitor AEFIs in Victoria, Australia. Data from SAEFVIC was used in conjunction with records of subsequent immunisation visits to determine if any subsequent episodes of apnoea AEFI occurred. 

Of the 48 eligible infants, two were excluded; one infant was lost to follow-up, and the other was >12 months old at the time of subsequent vaccination.

Of the 46 infants included in the study, 38 were preterm, of whom 7 experienced a recurrence of apnoea AEFI with subsequent vaccination, and 1 suffered a hypotonic-hyporesponsive episode AEFI; the remaining 30 infants had no recurrence. The recurrence rate for preterm infants was 18% (95% CI: 6–31%). Potential risk factors identified for apnoea AEFI in preterm infants were low birth weight (p=0.04) and ongoing hospitalisation for complications related to prematurity (p=0.001). Of the 8 term infants included in the study, none suffered a recurrence.

The authors discuss the importance of supporting the families of infants who have suffered previous apnoea AEFI in completing the immunisation schedule, and that understanding potential risk factors will help inform protocol for safe observation of subsequent vaccinations for these infants. The authors recommend that preterm infants who experience apnoea AEFI should receive reliable cardiorespiratory monitoring for a minimum of 24 hours following the next scheduled vaccination. 

Presented by Kerrie Wiley, PhD student – Social Research, NCIRS

Clinical efficacy of cell culture-derived and egg-derived inactivated subunit influenza vaccines in healthy adults

Frey S, Vesikari T, Szymczakiewicz-Multanowska AM, et al. 
Clinical Infectious Diseases 2010;51(9):997-1004
Link to abstract

The production and immunogenicity and safety testing of egg-based influenza vaccines normally takes half a year. Vaccine production and testing technology needs to continue to improve to shorten this period. Frey et al conducted a randomised controlled trial (RCT) assessing the immunogenicity, efficacy and safety of cell culture-derived influenza vaccine (CCIV) using the egg-based trivalent inactivated vaccine (TIV) and saline as controls. 

The study included more than 11,000 subjects aged 18–49 years in the USA, Finland and Poland during the 2007–08 influenza season. Around 3,800 of the participants received CCIV, 3,600 were given TIV and the rest received placebo (saline). Seroprotection, seroconversion rates, and anti-haemagglutinin geometric mean titres were determined on day 1 and 3 weeks after vaccination. During the 6-month follow-up period, nose and/throat swabs were collected from subjects with influenza-like illness and tested by PCR and/or culture. The efficacy of CCIV against all circulating influenza virus strains was 69.5% while the efficacy of TIV was 63.0%. Immunogenicity of both CCIV and TIV achieved the criteria of the Center for Biologics Evaluation and Research. Both vaccines were well tolerated. No vaccination-related serious adverse events were found.

The trial by Frey was one of the largest RCTs evaluating the efficacy of TIV and was the first to examine the efficacy of a cell culture-derived vaccine. Both CCIV and TIV appeared to be effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains. They were well tolerated, and had good safety profiles. The time of vaccine production may be shortened by using the cell-based influenza vaccine.

Presented by Kevin Jiehui Yin, Research Officer/PhD Candidate, NCIRS

Reduced intradermal test dose of yellow fever vaccine induces protective immunity in individuals with egg allergy

Roukens AH, Vossen AC, van Dissel JT, Visser LG. 
Vaccine 2009;27(18):2408-9
Link to abstract 

This study follows on from a previous study* by the same authors who found that an intradermal dose of yellow fever vaccine produced protective immunity in healthy, non-allergic subjects. 

The yellow fever 17D (YF-17D) vaccine strain is propagated on embryonated chicken eggs and consequently the vaccine contains a small amount of egg protein. In Holland, where this study was conducted, the protocol for yellow fever vaccination in a person with history of egg allergy involves giving a test dose, 0.1 mL of the vaccine administered intradermally. The test is read after 30 minutes. If there is a positive reaction (i.e. weal greater than twice the size of the control) further vaccination is abandoned. The authors obtained serum from 7 of 11 patients who had received the test dose and developed positive reactions at the outpatient travel clinic of the Leiden University Medical Center. 

Neutralising antibodies were measured by constant virus-varying serum dilution Plaque Reduction Neutralisation Test. The sera from all 7 patients showed levels of neutralising antibody indicative of protection. There were no adverse reactions to the test dose in the 7 patients other than the local weal formation. 

The authors conclude that a test dose of 0.1 mL of YF-17D vaccine appears to be sufficient for production of protective antibodies in non-allergic as well as allergic persons. However, they admit that the sample size of this study was too small to conclude that post-vaccination testing would no longer be necessary after an intradermal test dose.

* Roukens AH, Vossen AC, Bredenbeek PJ, et al. Intradermally administered yellow fever vaccine at reduced dose induces a protective immune response: a randomized controlled non-inferiority trial. PLoS ONE 2008;3(4):e1993.

Presented by Kath Cannings, Immunisation CNC, NCIRS