The Lancet Infectious Diseases
Dec 2015 Volume 15 Number 12 p1361-1498
http://www.thelancet.com/journals/laninf/issue/current

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Editorial
Tuberculosis reaches new milestones, good and bad
The Lancet Infectious Diseases
DOI: http://dx.doi.org/10.1016/S1473-3099(15)00431-4
Summary
The 20th instalment of WHO’s Global tuberculosis report was published on Oct 28, 2015, heralded by the headline that tuberculosis mortality had nearly halved over the past 25 years. This positive news was closely followed by the sobering announcement that tuberculosis now ranks alongside HIV among the leading infectious causes of death, with the deaths of 1·5 million people being attributable to the disease. Most of these deaths could have been prevented; in fact, tuberculosis has been a curable disease since the 1950s.

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Comment
Neonatal rotavirus vaccination making headway
Timo Vesikari
Published Online: 26 August 2015
Summary
The randomised trial reported by Julie Bines and colleagues1 in The Lancet Infectious Diseases is a clear step forward in the long history of the Australian neonatal rotavirus vaccine. In 1983, Bishop and colleagues2,3 noted that children who had acquired a rotavirus infection in the neonatal period were protected against severe (but not mild) rotavirus diarrhoea later in life. The study had been made possible because a so-called nursery strain of rotavirus was circulating in a hospital in Melbourne, which was later identified as G3P2A[6] rotavirus and is the origin of the present vaccine designated as RV3-BB.

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Articles
Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial
Julie E Bines, Margaret Danchin, Pamela Jackson, Amanda Handley, Emma Watts, Katherine J Lee, Amanda West, Daniel Cowley, Mee-Yew Chen, Graeme L Barnes, Frances Justice, Jim P Buttery, John B Carlin, Ruth F Bishop, Barry Taylor, Carl D Kirkwood, RV3 Rotavirus Vaccine Program
Summary
Background
Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth.
Methods
This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0–5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0–5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943.
Findings
95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55–0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44–0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo.
Interpretation
RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines.
Funding
Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.

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Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial
Michael T White, Robert Verity, Jamie T Griffin, Kwaku Poku Asante, Seth Owusu-Agyei, Brian Greenwood, Chris Drakeley, Samwel Gesase, John Lusingu, Daniel Ansong, Samuel Adjei, Tsiri Agbenyega, Bernhards Ogutu, Lucas Otieno, Walter Otieno, Selidji T Agnandji, Bertrand Lell, Peter Kremsner, Irving Hoffman, Francis Martinson, Portia Kamthunzu, Halidou Tinto, Innocent Valea, Hermann Sorgho, Martina Oneko, Kephas Otieno, Mary J Hamel, Nahya Salim, Ali Mtoro, Salim Abdulla, Pedro Aide, Jahit Sacarlal, John J Aponte, Patricia Njuguna, Kevin Marsh, Philip Bejon, Eleanor M Riley, Azra C Ghani
1450
Open Access
Summary
Background
The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.
Methods
Using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.
Findings
RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity.
Interpretation
Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.
Funding
UK Medical Research Council.

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Cost-effectiveness of high-dose versus standard-dose inactivated influenza vaccine in adults aged 65 years and older: an economic evaluation of data from a randomised controlled trial
Ayman Chit, Debbie L Becker, Carlos A DiazGranados, Michael Maschio, Eddy Yau, Michael Drummond
Summary
Background
Adults aged 65 years and older account for most seasonal influenza-related hospital admissions and deaths. Findings from the randomised controlled FIM12 study showed that high-dose inactivated influenza vaccine is more effective than standard-dose vaccine for prevention of laboratory-confirmed influenza in this age group. We aimed to assess the economic impact of high-dose versus standard-dose influenza vaccine in participants in the FIM12 study population.
Methods
The FIM12 study was a head-to-head randomised controlled trial in which 31 989 participants aged 65 years and older were randomly assigned (1:1) to receive either high-dose or standard-dose trivalent inactivated influenza vaccine over two influenza seasons (2011–12 and 2012–13). Data for health-care resource consumption obtained in the FIM12 study were summarised across vaccine groups. Unit costs obtained from standard US cost sources were applied to each resource item, including to the vaccines (high dose US$31·82, standard dose $12·04). Clinical illness data were mapped to existing quality-of-life data. The time horizon was one influenza season; however, quality-adjusted life-years (QALYs) lost due to death during the study were calculated over a lifetime. We calculated incremental cost-effectiveness ratios (ICERs) for high-dose versus standard-dose vaccine and used QALYs as an outcome in the cost-utility analysis. We undertook a probabilistic sensitivity analysis using bootstrapping to explore the effect of statistical uncertainty on the study results.
Findings
Mean per-participant medical costs were lower in the high-dose vaccine group ($1376·72 [SD 6857·59]) than in the standard-dose group ($1492·64 [7447·14]; difference –$115·92 [95% CI −264·18 to 35·48]). Mean societal costs were likewise lower in the high-dose versus the standard-dose group ($1506·48 [SD 7305·19] vs $1634·50 [7952·99]; difference −$128·02 [95% CI −286·89 to 33·30]). Hospital admissions contributed 95% of the total health-care-payer cost and 87% of the total societal costs. The mean per-participant number of hospital admissions was 0·0937 (SD 0·3644) in the high-dose group and 0·1017 (0·3708) in the standard-dose group (difference −0·0080, 95% CI −0·0160 to −0·0003). The high-dose vaccine provided a gain in QALYs (mean 8·1502 QALYs gained per participant [SD 0·5693]) compared with the standard-dose vaccine (8·1499 QALYs [0·5697]) and, due to cost savings, dominated standard-dose vaccine in the cost-utility analysis. The probabilistic sensitivity analysis showed that the high-dose vaccine is 93% likely to be cost saving.
Interpretation
High-dose trivalent inactivated influenza vaccine is a less costly and more effective alternative to the standard-dose vaccine, driven by a reduction in the number of hospital admissions. These findings are relevant to US health-care beneficiaries, providers, payers, and recommending bodies, especially those seeking to improve outcomes while containing costs.
Funding
Sanofi Pasteur.