A threshold method for immunological correlates of protection

BMC Medical Research Methodology (Impact Factor: 2.27). 03/2013; 13(1):29. DOI: 10.1186/1471-2288-13-29
Source: PubMed

ABSTRACT Background
Immunological correlates of protection are biological markers such as disease-specific antibodies which correlate with protection against disease and which are measurable with immunological assays. It is common in vaccine research and in setting immunization policy to rely on threshold values for the correlate where the accepted threshold differentiates between individuals who are considered to be protected against disease and those who are susceptible. Examples where thresholds are used include development of a new generation 13-valent pneumococcal conjugate vaccine which was required in clinical trials to meet accepted thresholds for the older 7-valent vaccine, and public health decision making on vaccination policy based on long-term maintenance of protective thresholds for Hepatitis A, rubella, measles, Japanese encephalitis and others. Despite widespread use of such thresholds in vaccine policy and research, few statistical approaches have been formally developed which specifically incorporate a threshold parameter in order to estimate the value of the protective threshold from data.

We propose a 3-parameter statistical model called the a:b model which incorporates parameters for a threshold and constant but different infection probabilities below and above the threshold estimated using profile likelihood or least squares methods. Evaluation of the estimated threshold can be performed by a significance test for the existence of a threshold using a modified likelihood ratio test which follows a chi-squared distribution with 3 degrees of freedom, and confidence intervals for the threshold can be obtained by bootstrapping. The model also permits assessment of relative risk of infection in patients achieving the threshold or not. Goodness-of-fit of the a:b model may be assessed using the Hosmer-Lemeshow approach. The model is applied to 15 datasets from published clinical trials on pertussis, respiratory syncytial virus and varicella.

Highly significant thresholds with p-values less than 0.01 were found for 13 of the 15 datasets. Considerable variability was seen in the widths of confidence intervals. Relative risks indicated around 70% or better protection in 11 datasets and relevance of the estimated threshold to imply strong protection. Goodness-of-fit was generally acceptable.

The a:b model offers a formal statistical method of estimation of thresholds differentiating susceptible from protected individuals which has previously depended on putative statements based on visual inspection of data.

Download full-text


Available from: Fabrice Bailleux, Apr 02, 2014
1 Follower
26 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Because of concern about safety and efficacy, no pertussis vaccine has been included in the vaccination program in Sweden since 1979. To provide data that might permit the reintroduction of a pertussis vaccine, we conducted a placebo-controlled trial of two acellular and one whole-cell pertussis vaccines. After informed consent was obtained, 9829 children born in 1992 were randomly assigned to receive one of four vaccines: a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (2566 children), a five-component acellular DTP vaccine (2587 children), a whole-cell DTP vaccine licensed in the United States (2102 children), or (as a control) a vaccine containing diphtheria and tetanus toxoids (DT) alone (2574 children). The vaccines were given at 2, 4, and 6 months of age, and the children were then followed for signs of pertussis for an additional 2 years (to a mean age of 21/2 years). The whole-cell vaccine was associated with significantly higher rates of protracted crying, cyanosis, fever, and local reactions than the other three vaccines. The rates of adverse events were similar for the acellular vaccines and the control DT vaccine. After three doses, the efficacy of the vaccines with respect to pertussis linked to a laboratory-confirmed case of pertussis or contact with an infected household member with paroxysmal cough for > or = 21 days was 58.9 percent for the two-component vaccine (95 percent confidence interval, 50.9 to 65.9 percent), 85.2 percent for the five-component vaccine (95 percent confidence interval, 80.6 to 88.8 percent), and 48.3 percent for the whole-cell vaccine (95 percent confidence interval, 37.0 to 57.6 percent). The five-component acellular pertussis vaccine we evaluated can be recommended for general use, since it has a favorable safety profile and confers sustained protection against pertussis. The two-component acellular vaccine and the whole-cell vaccine were less efficacious.
    New England Journal of Medicine 03/1996; 334(6):349-55. DOI:10.1056/NEJM199602083340602 · 55.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine if respiratory syncytial virus (RSV) specific, serum antibody titers correlate with protection against RSV associated-hospitalization at all ages. Participants who were enrolled in a trial to determine the frequency of specific virus infections associated with hospitalization [J. Am. Med. Assoc. 283 (2000) 499] were included in our analysis if they were enrolled from July 1991 to June 1993, had a culture for virus isolation, and provided blood samples at hospitalization and 14-60 days later. RSV infection was defined by a positive culture and/or serology. Microneutralization, ELISA to the fusion (F) protein and Western blot were the serological assays that were used to determine correlates of immunity. One hundred and seventy-five individuals, 1 month to 89 years old, out of 538 patients hospitalized with an acute respiratory infection met the criteria for analysis. RSV associated-hospitalization occurred in 11 (40.7%) of 27 infants (<1 year), 8 (38.1%) of 21 young children (1 to <5 years), and 15 (11.8%) of 127 children and adults (> or =5 years). At the time of hospitalization, geometric mean neutralizing antibody titers (log(2)) to RSV/A and RSV/B, and geometric mean binding antibody titer (log(2)) to F protein were significantly higher in patients with non-RSV associated-hospitalization compared to those with RSV associated-hospitalization (RSV/A: 7.9 versus 6.1, P<0.001; RSV/B: 9.4 versus 7.3, P<0.001; ELISA-F, 13.9 versus 12.6, P=0.01). For every 1 log(2) increase in titer of neutralizing antibodies to RSV/A and RSV/B, and binding antibody to F protein there was a significant increase in the likelihood of not having an RSV associated-hospitalization by 22.3, 25, and 24.4% respectively. A minimal protective threshold titer of > or =6.0 (odds ratio 3.5; 95% CI 1.4-9.1) and > or =8.0 log(2) (odds ratio 2.9; 95% CI 1.1-7.7) against RSV associated-hospitalization was established for neutralizing antibodies to RSV/A and RSV/B; a threshold titer could not be established for binding antibody to F protein. Participants with naturally acquired serum neutralizing antibody levels at least equal to the minimal protective threshold titer were approximately three times more likely not to have an RSV associated-hospitalization. We speculate that achieving a minimal protective threshold antibody titer through active immunization will significantly reduce RSV associated-hospitalization among all ages.
    Vaccine 08/2003; 21(24):3479-82. DOI:10.1016/S0264-410X(03)00355-4 · 3.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Four thousand forty-two healthy children and adolescents, ages 12 months to 17 years, were vaccinated with a single dose of live attenuated varicella vaccine (VARIVAX; Merck Sharp and Dohme Research Laboratories) containing approximately 1000 to 1625 plaque-forming units/dose during clinical trials conducted from 1987 to 1989. Clinical follow-up of vaccinees revealed that 2.1 and 2.4% of vaccinees developed modified cases of varicella in the first and second years, respectively, after vaccination. Most of those who developed varicella postvaccination had an attenuated illness, characterized by fewer lesions and a lower incidence of fever (greater than or equal to 100 degrees F, oral) than after natural infection. The likelihood of developing varicella postvaccination decreased (P less than 0.0001) as the 6-week postvaccination glycoprotein-based enzyme-linked immunosorbent assay titer increased. In addition the number of lesions in these cases tended to decrease (P = 0.07 for Year 1 and P = 0.02 for Year 2) as the 6-week glycoprotein-based enzyme-linked immunosorbent assay titer increased. Thus the 6-week postvaccination glycoprotein-based enzyme-linked immunosorbent assay titer can be used as a surrogate marker for protection from natural disease.
    The Pediatric Infectious Disease Journal 02/1992; 11(1):19-23. · 2.72 Impact Factor
Show more