In September, scientists from the Thailand Ministry of Public Health, in collaboration with the U.S Army, hailed a breakthrough in research towards a HIV vaccine….a positive result. Now, the full results by Rerks-Ngarm and colleagues, published on 20th October in the New England Journal of Medicine, reveal that the outcome of the trial was not so positive after all…..in fact it was statistically insignificant (i.e. the results could have happened by chance).
The $105 million RV144 HIV/AIDS vaccine clinical trial included more than 16,400 volunteers aged 18 – 30 yrs old. Half were randomly picked to receive a combination of two HIV vaccines (ALVAC and AIDSVAX) whilst the rest received a placebo vaccine. The volunteers were monitored after a 6 month vaccination programme and every 6 months for a further 3 years. On the 24th September, the world media reported that the ALVAC-AIDSVAX combo was the first experimental vaccine to have a statistically significant effectiveness (~31%) at reducing the risk of HIV infection.
However, following the publication of the full analysis of the results last week the response from the scientific world has been somewhat muted. The scientists from the study themselves state that the results show only a “modest benefit” and reveal a 26% effectiveness at reducing the risk of HIV infection which was statistically insignificant (could have happened by chance). Also, the protective effects of the vaccine reduced after 12 months and the vaccine did not protect those at high risk of HIV infection (intravenous drug users and sex workers)
So how come there are two very different results within the same study? Basically, it is all down to which volunteers you include in the analysis of the results. The study started with 16,402 people who were randomly assigned to receive the vaccine or the placebo over the course of six months. However, 7 people were found to be already HIV-positive at the beginning and so were removed from the results. This meant that 8197 people received the HIV vaccine whilst 8198 received the placebo (16,395 total). During the course of the study, 2021 people were excluded from the results from the vaccine arm of the study and 1832 people were excluded from the results from placebo arm of the study. People were excluded for a number of reasons such as they were not given the full 6 doses of the vaccine during the course of the study, they were given the wrong dose of vaccine or were not given the vaccine in the correct time period. This meant that the final number of people that match all the experimental criteria for the study analysis was 6176 in the vaccine group and 6366 people in the placebo group (12,542 total).
The level of success of the vaccine depends on which set of people you pick to analyse:
- the “modified intention to treat” set are the 16,395 people at the beginning of the trial (discounting the 7 people who were HIV-positive). Analysis of their results gives you the statistically significant 31% effectiveness of the vaccine
- the “per protocol” set are the 12, 542 people at the end of the study who have received the correct dose and number of vaccines, and were HIV-negative during the course of the vaccination programme. Analysis of their results gives you the statistically insignificant 26% effectiveness of the vaccine.
The full results demonstrate just how difficult it is to interpret results from large clinical trials and the complexities in using statistical significance for confirming evidence-based research. The full analysis of the people who received the correct number of vaccines and the correct dose during the correct time period suggests that the ALVAC-AIDSVAX vaccine trial was not successful and more work is needed to find that elusive protective HIV vaccine.
Treating vaccinated children with paracetamol as a precautionary measure against fever may reduce the effectiveness of the vaccine itself, according to research by Prymula et al. published in The Lancet on the 17th October.
Fever is classed as a temperature of over 38oC and is a normal part of the inflammatory response to infection, and after vaccination. Fever is worrying in children because of the risk of febrile convulsions (seizures that occur in children with a high temperature). Some countries recommend antipyretic drugs (drugs that reduce the body temperature), like paracetamol, after vaccination in children with a history of febrile convulsions. However, evidence to support their use is scare.
The Czech and Swiss researchers performed a randomised, controlled trial of 459 children receiving primary and booster vaccinations against a combination of common childhood diseases (including vaccines for whooping cough, diphtheria, rotavirus, tetanus) in ten centres across the Czech Republic to test the effects paracetamol during vaccination. Approximately half the children received three doses of paracetamol every 6-8 hours over the 24 hours post-vaccination, whilst the rest did not receive any paracetamol. Treatment with paracetamol after vaccination significantly reduced fever in children, but also significantly lowered antibody responses (including those against tetanus and diphtheria) to several of the vaccine antigens (meaning the vaccine does not produce as effective a protective immune response). The study also showed that high fever (> 39.5oC) is actually a rare event after vaccination, both treatment groups had 2% or less children with a high fever after vaccination.
This research suggests that antipyretic drugs, like paracetamol, should not be routinely given to children after vaccination because it may interfere with how well the vaccine works. A linked article in the same issue of The Lancet discusses some of the important implications following the results of this study. More is needed to understand just how paracetamol reduces the protective host immune response that occurs during vaccination, and whether other antipyretic drugs (such as ibruprofen) also have the same effects as paracetamol.
*The results of the study are listed in ClinicalTrials. gov, numbers NCT00370318 and NCT00496015.
Diarrhoeal disease is a significant global health problem. Every year there are ~4 billion cases, and 2.5 million deaths, from diarrhoea. Most of these cases are in developing countries, and the sad fact is each year 1.5 million children under five die from diarrhoea (that’s more than the childhood deaths caused by AIDS, malaria and measles combined). This makes diarrhoea the 2nd biggest killer of under fives globally. That’s 1.5 million under fives dying from a disease that can be easily, and cheaply treated, and in developed countries it is thought of as nothing more than the squits.
On 14th October, UNICEF and WHO published a new report “Diarrhoea: why children are still dying and what can be done” as part of a strategy to try and boost global efforts to fight childhood diarrhoea. Bacteria (such as Shigella and Vibrio cholerae), parasites (such as Crpytosporidium) and viruses (such as Rotavirus) all cause diarrhoeal disease. They are often spread in contaminated, dirty water via a faecal-oral route of transmission (that’s pathogens in faeces from one person transferred, via contaminated water or food, to the mouth). Also, limited access to medical care and malnutrition can make the burden of the disease worse. So, they’ve come up with a 7-point plan to treat and prevent childhood diarrhoea.
This plan is to:
- replace lost fluids to prevent dehydration (using the new improved low-osmolarity oral rehydration solution)
- include zinc treatment for diarrhoea (it reduces the severity and duration of diarrhoea, as well as reducing the likelihood of getting it again)
- rotavirus and measles vaccination
- promote exclusive breastfeeding (breastmilk is nutritious and provides crucial antibodies for infants to survive and develop) and vitamin A supplementation (it reduces childhood mortality and reduces the severity, duration and complications associated with childhood diarrhoea)
- promote handwashing with soap (this helps break the faecal-oral transmission route and reduces the incidence of diarrhoea by over 40%)
- improve access to clean water; improving the supply and quality as well as promoting safe household water treatment (including chlorination, filtration and solar disinfection) and storage
- promote sanitation in communities; especially approaches to change people’s attitudes to reduce open defecation (1.2 billion people practice open defecation worldwide)
This 7-point plan needs to be put in place in areas where it is needed the most; 80% of deaths from childhood diarrhoea occur in Africa and South Asia, with almost three quarters of these deaths in only 15 countries (the top four with the highest deaths from childhood diarrhoea are India, Nigeria, Democratic Republic of Congo and Afghanistan). Hopefully this 7-point plan will inspire governments, charities and non-governmental organisations to reduce childhood deaths from diarrhoea and help meet the Millennium Developmental Goals 4 (to reduce childhood mortality by two-thirds by 2015) and 7 (halve the number of people without access to safe drinking water and sanitation).
Scientists have found that the bacterium, Cupriavidus metallidurans, can transform toxic gold compounds to metallic gold, according to research by Reith and colleagues published online on the 7th October in the journal PNAS.
Bacteria are naturally found on gold particles from the earth’s surface; but it is unclear, and controversial, as to whether bacteria have an active role in the formation of these gold particles (biomineralisation). An international team of scientists (from Australia, USA, Canada, Germany, Belgium and France) investigated a metallophilic (metal resistant and able to grow on heavy metals) bacterium called Cupriavidus metallidurans, which forms biofilms (a slimy layer of bacteria stuck together) on grains of gold. They found that C. metallidurans accumulates toxic gold complexes (containing Au III ions) from solution inside the bacterial cell, this accumulation is increased in metabolically active (i.e. living) bacteria. The toxic gold complexes activate bacterial genes involved in the combat against oxidative stress (damage in cells caused by reactive oxygen species, which includes unpaired electrons aka free radicals), and for metal resistance. Also, an uncharacterised cluster of genes which are specifically linked with resistance to gold were activated. Bacteria were then able to detoxify these gold complexes, ultimately turning them into harmless nanoparticles of gold. Similar gold nanoparticles were also seen in bacterial biofilms on grains of gold.
C. metallidurans containing a gold nanoparticle. Reith et al (PNAS 2009).
The scientists used some very fancy and expensive equipment for their work; including synchotrons at the European Synchotron Radiation Facility (ESRF) and the Advanced Photon Source (APS). Synchotrons are a type of particle accelerator that produces very intense beams of X-rays (1000 billion times brighter than X-rays in hospitals). They were used by the scientists as a super-microscope to see gold particles inside C. metallidurans in great detail.
These findings provide evidence that bacteria in the environment may contribute to the formation of grains of gold, which in turn could form gold nuggets. Gold is a rare and precious metal and these bacteria could be used as a tool to help mineral explorers find new gold deposits.
So it’s award season in the scientific world………and it’s a biggie….The Nobel Prize. Every year since 1901 the Nobel Prize has been awarded for physics, chemistry, physiology or medicine, literature and for peace, and from 1968 the Sveriges Riksbank Prize for Economic Sciences was also introduced. Winners take home a medal, a diploma and a big fat cheque for 10m Swedish Kronor (~£800,000)…oh and the small bonus of international recognition for your life’s hard work.
So this year the science gongs go to:
- Nobel Prize for Physiology or Medicine; jointly to Elizabeth H. Blackburn (University of California, USA), Carol W. Greider (John Hopkins University, USA) and Jack W. Szostak (Harvard Medical School, USA) for the discovery of “how chromosomes are protected by telomeres and the enzyme telomerase”
- Nobel Prize for Physics; half to Charles K. Kao (Standard Telecommunication Technologies and the Chinese University of Hong Kong, Hong Kong) for “groundbreaking achievements concerning the transmission of light in fibres for optical communication” and half shared between William S. Boyle and George E. Smith (both from Bell Laboratories, USA) for “the invention of an imaging semiconductor circuit- the CCD sensor”
- Nobel Prize for Chemistry; jointly to Venkatraman Ramakrishnan (MRC Laboratory of Molecular Biology Cambridge, UK), Thomas A. Steitz (Yale University, USA) and Ada E. Yonath (Weizmann Institute of Science, Israel) for “studies of the structure and function of the ribosome”.
In layman’s terms that is;
- Physiology of Medicine; understanding how the ends of DNA molecules are maintained (“just like the plastic tips on shoelaces”) which has important implications for cancer and ageing.
- Physics; revolutionising modern communications by transmitting light along glass fibres over huge distances (it’s how we get our broadband) and the CCD is the eye of digital cameras (it’s in the camera in our mobile phones).
- Chemistry; understanding the mechanism of how cells make proteins, which is absolutely fundamental to life.
Now, let’s not forget the other important prize of the year…..The Ig Nobel’s (the website alone is worth a look for the picture of Nobel Laureates wearing one of this year’s inventions, a bra/facemask, and a video about the first recorded case of a homosexual necrophiliac duck….yes really).
2009 Ig Nobel Prize Ceremony. Left to right; Wolfgang Ketterle, Elena Bodnar, Orhan Pamuk and Paul Krugman. Photo; Alexey Eliseev
The “Igs” are awarded to scientists whose work “first makes people laugh, and then makes people think”. This year’s highlights include prizes for:
- Peace; shared between Stephan Bolliger, Steffen Ross, Lars Oesterhelweg, Michael J. Thali and Beat P. Kneubuehl from the University of Bern (Switzerland), for their work on whether it is better to be smashed over the head with a full or empty bottle of beer.
- Veterinary Medicine; shared between Catherine Douglas (nee Bertenshaw) and Peter Rowlinson from Newcastle University (UK), for their work showing that dairy cows given a name produce more milk.
- Physics; shared between Katherine K. Whitcome (University of Cincinnatti, USA), Daniel E. Lieberman (Harvard University, USA) and Liza J. Shapiro (University of Texas, USA), for their analysis of how pregnant women stay upright and don’t topple over all the time.
- Biology; shared between Fumiaki Taguchi, Song Guofu, and Zhang Guanglei from Kitasato University (Japan) for their work showing that bacteria from giant panda poo can reduce kitchen waste mass by 90%.