MICA:The immunogenicity of combined pertussis-containing vaccine (Tdap) for HIV-infected pregnant women and their newborns-A Randomized Clinical Trial

This study will work out whether vaccinating pregnant women in Uganda with a pertussis (whooping cough) vaccine might be useful to help prevent babies in Uganda from becoming ill or dying with whooping cough.

Babies in countries like Uganda are usually vaccinated against pertussis at 10, 14 and 16 weeks of age, and until these injections are completed, babies are at risk of getting pertussis infection and becoming unwell or dying. Until a baby is fully vaccinated, they rely on their own immature blood cells and also protection passed across the placenta in the form of antibodies from their mother during pregnancy.

One way that we could protect these vulnerable babies is by vaccinating pregnant women with a whooping cough vaccine called Tdap, to increase the antibody levels in the mother's blood so that more protection can pass across the placenta into the baby. This is already being done in countries like the U.S and the U.K, and we know it is effective in reducing the number of babies becoming sick with whooping cough. The WHO has recommended that Tdap be offered to pregnant women around the world. However, there are no studies looking at whether giving the vaccine in countries like Uganda, where there is a high burden of HIV disease, will work in the same way.

We know that vaccinating a pregnant woman with pertussis vaccine may reduce a baby's response to their own vaccines, which could leave the baby unprotected. However, babies in Uganda receive a different type of pertussis vaccine (wP) to the one used for babies in the U.K/U.S. This vaccine is thought to be more effective in countries where there is a lot of pertussis. We do not know if the same reduced protective effect occurs in countries giving wP vaccine.

Many factors affect how much protection is passed from a mother to her baby during pregnancy. A very important factor is whether or not the mum has HIV infection. Around 10% of pregnant women in Uganda have HIV and so we need to see if a mother with HIV has the same response to the whooping cough vaccine as a mother without HIV, and whether they pass the same amount of protection to their babies.

We will study these important questions by asking a group of HIV-infected and HIV-uninfected pregnant women to be part of our vaccine trial. We will vaccinate half of each group with tetanus and whooping cough vaccines, and half of each with the routine tetanus vaccine, which pregnant women in Uganda already receive. We will then measure the antibody levels in the mothers' blood at the time of delivery and the antibody levels in the baby's umbilical cord blood. We can then measure how much antibody is passed from mothers to their babies. We will compare the antibody levels between HIV-negative and HIV-positive women. We will then follow-up all the babies, and measure their whooping cough antibody responses at the end of their routine vaccination course, to find out whether vaccinating their mothers has influenced the infant's protection levels.

Throughout this 24 month study in Uganda we will answer the following questions to help decide whether maternal vaccination should be used to protect the most vulnerable babies in countries like Uganda:
1) Do pregnant women with HIV have lower antibody responses to immunization with tetanus, diphtheria, acellular pertussis (Tdap) vaccine, compared to HIV-uninfected women?
2) Does immunization with Tdap vaccine in pregnancy influence the amount of antibody an infant makes following the whole cell pertussis (wP) vaccine in babies.

Maternal vaccination with Tdap is routine in high income countries and recommended by the WHO for low and middle-income settings. However, there is currently no evidence of efficacy in high HIV-burden settings, hampering vaccine implementation. This study aims to investigate the effect of maternal HIV infection on the immune response to tetanus, diphtheria, acellular pertussis (Tdap) immunization in pregnant women and will look at whether Tdap vaccination in pregnancy influences the infants' immune response following immunization with whole cell pertussis (wP) vaccine.
We plan a phase IIb intervention randomised observer blind clinical trial of Tdap vaccine in pregnancy and wP vaccine in infancy at Mulago Hospital, Kampala in 94 HIV-infected and 94 HIV-uninfected women. Women will be randomised to receive either routine care (tetanus toxoid vaccine) plus Tdap or routine care vaccinations alone.
We will collect baseline, 4 weeks post-vaccination and post-delivery blood from women and cord blood. We will follow infants until 18 weeks of age taking a final blood sample 4 weeks after 3 doses of wP vaccine. We will perform multiplex Luminex assays to determine antibody concentrations followed by avidity and serum bactericidal assays to determine antibody function, as it is known that HIV infection confers a hypergammaglobulinaemic but poorly functional antibody state. The data from these experiments will be analysed to determine the non-inferiority of Tdap vaccine in HIV-infected compared to HIV-uninfected women. We will investigate placental antibody transfer and wP antibody concentrations to demonstrate the effect of Tdap in pregnancy on infant wP responses. Finally, we will determine the correlation between Tdap antibody concentration and function in HIV-exposed and unexposed infants and their mothers. The results are of interest to industry, policy makers and regulators, all of whom have already been involved as stakeholders in the development of our proposal.

Pertussis or whooping cough is a respiratory disease mainly caused by the Gram-negative coccobacillus Bordetella pertussis with highest morbidity and mortality rates among infants that have received either no or incomplete vaccination. Pertussis has resurged as a major public health concern in many countries. Until two decades ago, the control of the disease was mainly carried out through a vaccination scheme consisting of a three-dose primary series. In order to accomplish this, two types of vaccines are currently available: a whole-cell vaccine based on standardized cultures of B. pertussis strains (wP) and an acellular form [acellular pertussis (aP)] composed of purified B. pertussis immunogens. Unfortunately, the duration of the immunity conferred by these two vaccines is not lifelong. Moreover, recent data indicated that protection from aP vaccines wears off faster than that induced by wP vaccines. This weakness in the current vaccines together with the lack of optimal vaccination coverage have contributed to the recent rise in pertussis incidence and fatalities.

Maternal pertussis immunization during the third trimester of every pregnancy is one of the recent strategies recommended in several countries to improve pertussis control in infants. The reported safety of the acellular vaccine when used during pregnancy and the placental transfer of pertussis antibodies from mothers to their infants argue in favor of this strategy. Nevertheless, the question of whether or not this approach is able to effectively protect neonates against pertussis in the context of HIV-infection and how the transmitted maternal immunity affects the protection conferred by subsequent infant wP vaccination are still insufficiently clear.
This clinical trial aims to plug these gaps by providing immunogenicity data following Tdap vaccination in pregnancy from a high HIV-burden setting using standardised assays developed by co-applicants investigating serocorrelates of protection against pertussis infection.

The outcomes of this research will be of direct interest to industrial partners (BioNet), but also to other industrial colleagues with whom we have close working relationships (GSK, Sanofi) all of whom have licenced Tdap vaccines for high and low resource settings. All data will be made available as soon as possible in a freely available and widely accessible format as per MRC policies to enable data analysis across platforms and to compare results from different studies. In this way, it is anticipated that the impact may be achieved through sharing of data developed from standardised assays that measure not only quantity, but more importantly function of these antibodies needed for infant protection.

The close collaboration with WHO through membership of co-applicants (Prof. Gorringe, Heath and Dr Le Doare and Sadarangani) on advisory panels will ensure that national and international policy-makers are kept fully informed of the immunogenicity results as we progress. We anticipate annual stakeholder meetings to present our findings. Additionally, the data generated from Uganda will be of direct benefit to the Ugandan government in deciding whether a Tdap vaccine can be adopted onto the extended programme on immunisation country schedule. The results of this work will also be available to Global Alliance for Vaccines Initiative to inform vaccine cost-effectiveness analyses as maternal vaccine strategies progresses.

Most importantly, though, the results of this programme of research will directly benefit pregnant women and their infants in Uganda, by providing the most comprehensive information on maternal Tdap vaccination in pregnancies affected by HIV to date.