Sunday, November 18, 2012

Malaria vaccines

I just returned from the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) where I attended symposia and scientific sessions on a number of topics including multidrug resistant tuberculosis, rabies, polio eradication, and child health. I also attended several presentations on malaria and dengue vaccines.

You may have heard about malaria vaccines in the news. The Bill and Melinda Gates Foundation has been funding malaria vaccine research and there have been some successes and some disappointing results reported in the news.

Although it's the American Society of Tropical Medicine and Hygiene, scientists from around the world come to ASTMH meetings to present their research. There are a number of malaria vaccines in various stages of development; some of them are in preclinical (animal) trials and some in clinical (human) trials. There are no malaria vaccines licensed or approved for use and none are available to the public.

Niger River, Mali 1988
Malaria is a disease with which I am fascinated and for which I have tremendous respect – it nearly killed me the second time I had it. I could spend several pages discussing malaria, but it's a complex disease with complex interactions between humans, mosquitoes, and the environment and, as much as I enjoy talking about malaria, I won't go into that level of detail here. I have included some links to webpages on malaria at the end of this post.


About half of the world's population lives in areas where malaria is transmitted. The World Health Organization estimates that there were about 216 million cases of malaria worldwide in 2011 and that around 655,000 malaria deaths in 2010, most of them children under five years of age in sub-Saharan Africa. Although that's down from over a million malaria deaths every year, some researchers believe that the annual number of malaria deaths is underestimated. That's not surprising considering that many of those deaths occur in rural areas of developing countries and are not reported to health authorities.


When I've mentioned that I've had malaria, people have said to me, "You must have drunk the water," "You must not have gotten the vaccine," or, "I heard that once you have it you have it for life," so it seems to me that there is some confusion about malaria – which doesn't surprise me.

Malaria is caused by a protozoan parasite which is transmitted through mosquito bites. Different species of Plasmodium infect humans, other mammals, birds, and reptiles. There a four species of human malaria: P. falciparum, P. malariae, P. ovale, and P. vivax. Humans can also be infected with P. knowlesi, a monkey malaria. P. ovale and P. vivax can cause relapses months to years after the first infection and people can have subclinical P. malariae infections for decades, but all of the species are curable, so "once infected, always infected" is not necessarily true.

Most malaria deaths and severe malaria infections are caused by P. falciparum. In addition to its severity and lethality, P. falciparum has developed resistance to almost every drug used to prevent and treat infection. For these reasons, most of the malaria vaccines that are in development are against P. falciparum.

The malaria parasite has several mechanisms by which it evades the human immune system. These create challenges for malaria vaccine developers. I will briefly discuss two of them:

Malaria lifecycle

The malaria parasite lifecycle includes several stages in both vertebrate and mosquito hosts. The parasite expresses different antigens at each stage of its lifecycle so that an immune response against one stage of the parasite will not "recognize" the parasite at a different stage.
 
 
Most cells in the body are able to signal cytotoxic lymphocytes that they are infected. These white blood cells can then kill the infected cell and the infecting agent along with it. The malaria parasite spends most of its time in the human body inside hepatocytes (liver cells) and erythrocytes (red blood cells), two types of cells that lack the ability to notify the immune system that they are infected with the parasite. The two extracellular (outside of cells) stages, sporozoites and merozoites, are present in the blood for a very short time, which limits their exposure to antibodies against them.

Immunity to malaria

Humans do not develop sterilizing immunity to malaria, that is, people who have been infected with malaria can have it again. The most effective immune responses are against proteins that are made by the parasite and expressed on the surface of infected red blood cells. The problem is, the parasite has genes that allow it to change those surface antigens and make infected cells unrecognizable to the immune system.

People who live in areas where malaria is transmitted develop a repertoire of antibodies against P. falciparum erythrocyte membrane protein 1 (PfEMP1). This keeps the number of infected blood cells low so that the person can be infected with the parasite but have relatively minor symptoms or no symptoms at all ("partial immunity").

People who live in endemic areas remain partially immune to malaria as long as they continue to be periodically infected with the parasite. Once a person is no longer exposed to malaria (e.g., moves someplace where malaria is not transmitted), she or he loses immunity and becomes susceptible to severe malaria again. A large proportion of cases of malaria in the U.S. are in people who came from malaria-endemic countries, lived in the U.S., and then returned to their country of origin to visit friends and relatives (VFR), thinking that they were still protected against malaria and did not need to take malaria prophylaxis.

Malaria vaccines



Mosquito injecting sporozoites
CDC
Researchers must choose a parasite antigen to which the human body will develop an adequate immune response. So far, the most successful vaccines have been against sporozoites, the infective stage of the parasite that is injected into the blood with mosquito saliva. Vaccines against other parasite stages have been developed, including transmission blocking vaccines which stimulate the immune system to produce antibodies that are ingested by the mosquito and prevent parasite development in the mosquito gut. These vaccines do not directly prevent human infection and disease but, theoretically, prevent transmission from an infected person to an uninfected person.
RTS,S is a sporozoite antigen vaccine in phase III trials which test how well the vaccine prevents disease in people who live in malaria endemic areas. Results of a study in African children 5 to 17 months of age and African infants 6 to 12 months of age (presented at the ASTMH meeting this year) demonstrated that RTS,S provides modest protection against malaria in children who received three doses of the vaccine.

While the press has called these results "disappointing" because the vaccine did not protect against malaria as well as had been hoped, these are positive results against an elusive pathogen. Even a modest reduction in malaria burden can save thousands of lives. I think it's also important to remember that current vaccines prevent bacterial and viral infections. This is the first vaccine against a protozoan pathogen.

Further RTS,S trials in different populations and using different dosing schedules are ongoing as are trials of other malaria vaccine candidates.


More information

References

Fairhurst, R. M. & Wellems, T. E. (2009). In G. L. Mandell, J. E. Bennett, & R. Dolin (Eds.) Mandell, Douglas, and Bennett's principles and practice of infectious diseases (7th ed.). Elsevier [Electronic version].

Holding, P. A., Snow, R. W. (2001). Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence. American Journal of Tropical Medicine and Hygiene, 64(Suppl. 1), 68-75. http://www.ajtmh.org/content/64/1_suppl/68.abstract.

Murray, C. J., Rodenfeld, L. C., Lim, S. S., Andrews, K. G., Foremen, K. J., Haring, D. et al. (2012). Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet, 379(9814), 413-431. http://www.ncbi.nlm.nih.gov/pubmed/22305225.

Plebanski, M., & Hill, A. V. S. (2000). The immunology of malaria infection. Current Opinion in Immunology, 12(4), 437-441. http://www.ncbi.nlm.nih.gov/pubmed/10899022.

The RTS,S Clinical Trials Partnership. (2011). First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children. New England Journal of Medicine, 365(20), 1863-1875. http://www.nejm.org/doi/full/10.1056/NEJMoa1102287.

The RTS,S Clinical Trial Partnership. (2012). A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. New England Journal of Medicine [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMoa1208394.

Sachs, J. & Malaney, P. (2002). The economic and social burden of malaria. Nature, 415(6872), 680-685. http://www.ncbi.nlm.nih.gov/pubmed/11832956.

Yazdani, S. S., Mukherjee, P., Chauhan, V. S., & Chitnis, C. E. (2006). Immune responses to asexual blood-stages of malaria parasites. Current Molecular Medicine, 6(2), 187-203. http://www.ncbi.nlm.nih.gov/pubmed/16515510.

 

Thursday, November 1, 2012

Hepatitis B


Andrew received his first hepatitis B vaccine minutes after he was born. There are several reasons for starting the hepatitis B vaccine series at birth. To understand them, we first need to understand the epidemiology and natural history of hepatitis B virus (HBV) infection.

Andrew shortly after receiving his first dose of hepatitis B vaccine

Hepatitis B virus transmission

Like human immunodeficiency virus (HIV), HBV is transmitted through blood and body fluids. Unlike HIV, HBV can survive outside of the human body and remain infectious over a week. HBV is also 50 to 100 times more infectious than HIV.

Worldwide, most HBV infections are acquired perinatally; that is, the virus was passed from an infected mother during childbirth. Infants who become infected with HBV are much less likely to develop symptoms of acute hepatitis B and much more likely to develop chronic HBV infection than adults who acquire the infection.

Age at infection:

Acute hepatitis B
Risk
Under 5 years of age
<10%
Over 5 years of age
30% to 50%
Chronic HBV infection
 
Infants
90%
1 to 4 years of age
30%
Adults
<5%

Transmission of HBV also occurs among household contacts of people with HBV infection, through sexual contact, through injection drug use, and is an occupational risk for people with frequent contact with blood and/or body fluids (e.g., health care providers. I was required to take the hepatitis B vaccine series when I started nursing school). Although hepatitis B was called "serum hepatitis" because it was frequently transmitted through blood transfusions, blood is now screened for hepatitis and other pathogens, so there is an extremely low risk of HBV infection from receiving a blood transfusion.

Hepatitis B infection

In my previous post on hepatitis, I briefly described the symptoms of acute hepatitis: jaundice, fatigue, malaise, muscle and joint pain, nausea and vomiting, and pain over the liver. Although fulminant liver failure can occur as a result of infection with any of the hepatotropic viruses (hepatitis A, B, C, D, and E viruses), most people recover from acute hepatitis without serious consequences.

People with chronic HBV infection can be completely asymptomatic for decades. Chronic HBV infection increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC, liver cancer). Babies can be infected at birth, show no signs of being infected, and then develop fatal liver disease later in childhood or as adults.

Hepatocellular carcinoma
CDC/Patricia Walker, M.D., Regions Hospital, MN
 
Cancer vaccine

Studies of hepatitis B vaccine have been ongoing since the 1980s. Vaccinating children against hepatitis B has reduced the incidence of HCC in children who received the vaccine in Taiwan, and Thailand and eliminated hepatitis B-associated HCC in Alaska Native children. For this reason, hepatitis B vaccine is considered the first cancer vaccine.

Vaccine safety

Hepatitis B vaccines contain a single viral surface antigen that is produced by yeast using recombinant DNA, similar to the way insulin (Humulin®, Novolin®) is made using yeast or the bacteria E. coli. Hepatitis B vaccines do not contain HBV and HBV is not used in the production of hepatitis B vaccines.

The safety of hepatitis B vaccines has been studied since the introduction of plasma-derived vaccines in the 1980s. The Institute of Medicine (IOM) has published two reviews of hepatitis B vaccine safety. The only adverse effect identified as causally associated with hepatitis B vaccines is a severe allergic reaction (anaphylaxis) in people who are allergic to yeast. This association was based on 10 cases of anaphylaxis in people who had received a hepatitis B vaccine. Another review of adverse reaction data found that hepatitis B vaccine-associated anaphylaxis in children is rare.

Why vaccinate babies against hepatitis B?

The most common way HBV is transmitted is from mother to child during childbirth. Babies who become infected with HBV are more likely to develop chronic HBV infection and less likely to have symptoms of acute hepatitis then older children and adults. Therefore, infancy is the most dangerous time to be infected with HBV. Immunizing babies against hepatitis B can prevent HBV infection and has been found to reduce the incidence of HCC in children.

The reason for universal immunization against hepatitis B can be found in the title of the Advisory Committee on Immunization Practices (ACIP) recommendations: A comprehensiveimmunization strategy to eliminate transmission of hepatitis B virus infection in the United States. I discussed disease eradication in and disease elimination previous posts. Disease elimination is "the reduction to zero of the incidence of infection caused by a specific agent in a defined geographical area as a result of deliberate efforts" (Dowdle, 1999); that is, transmission of the disease no longer occurs in a specific area of the world (in contrast to eradication, in which disease transmission no longer occurs anywhere in the world).

The study in Alaska demonstrated that HBV infection and HCC can be eliminated from a defined geographic region using universal childhood hepatitis B immunization. The incidence of HBV infection in children throughout the U.S. has decreased dramatically since the introduction of hepatitis B vaccines.
CDC, 2004


Mary 

Yesterday, the eve of All Saints Day, my mother-in-law Mary Esvelt died from a complication of the malignant brain tumor with which she was diagnosed on Mother's Day of this year.

I know of no person more dedicated to serving the Lord than Mary. She delighted in her ministries and teaching Christian belief and values.

I met the Esvelts while taking care of Seth, Holly's brother, who suffered a severe traumatic brain injury in a motor vehicle accident. Seth has remained in a minimally conscious state since the injury. Mary and Craig have cared for Seth at home 24/7 since Holly and I were married seven years ago.

Despite the physical pain she suffered from rheumatoid arthritis and the emotional pain of having a severely disabled son, Mary remained firm in her faith and tireless in her service to others. Mary was a blessing to all who knew her.

Of course, I admire Mary most for being the mother of my precious wife Holly.

"We do not want you to be unaware, brothers, about those who have fallen asleep, so that you may not grieve like the rest, who have no hope."
- 1 Thessalonians 4:13

References

Bohlke, K., Davis, R. L., Marcy, S. M., Braun, M. M., DeStefano, F., Black, S. B. et al. (2003). Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics, 112(4), 815-820. http://www.ncbi.nlm.nih.gov/pubmed/14523172.

Centers for Disease Control and Prevention. (2004). Incidence of acute hepatitis B – United States, 1990-2002. Morbidity and Mortality Weekly Report, 52(51 & 52), 1252-1254. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5251a3.htm.

Centers for Disease Control and Prevention. (2005). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: Immunization of infants, children, and adolescents. Morbidity and Mortality Weekly Report, 54(16), 1-23. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5416a1.htm.

Chang, M. H., You, S. L., Chen, C. J., Liu, C. J., Lee, C. M., Lin, S. M., et al. (2009). Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. Journal of the National Cancer Institute, 101(19), 1348-1355. http://jnci.oxfordjournals.org/content/101/19/1348.long.

Dowdle, W. R. (1999). The principles of disease elimination and eradication. Morbidity and Mortality Weekly Report, 48(Supple. 1), 23-27. http://www.cdc.gov/mmwr/preview/mmwrhtml/su48a7.htm.

Institute of Medicine. (2002). Hepatitis B vaccine and demyelinating neurological disorders. Washington D. C.: National Academies Press. http://books.nap.edu/catalog.php?record_id=10393.

Institute of Medicine. (2012). Adverse effects of vaccines: evidence and causality. Washington D.C.: National Academies Press. http://www.nap.edu/catalog.php?record_id=13164.

Kew, M. C. (2010). Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma. Pathologie Biologie, 58(4), 273-277. http://www.ncbi.nlm.nih.gov/pubmed/20378277.

Mast, E. E. & Ward, J. W. (2008). Hepatitis B vaccine. In S. A. Plotkin, W. A. Orenstein, & P. A. Offit (Eds.) Vaccines (5th Ed.) [Electronic version].

McMahon, B. J., Bulkow, L. R., Singleton, R. J., Williams, J., Snowball, M., Homan, C. et al. (2011). Elimination of hepatocellular carcinoma and acute hepatitis B in children 25 years after a hepatitis B newborn and catch-up immunization program. Hepatology, 54(3), 801-807. http://www.ncbi.nlm.nih.gov/pubmed/21618565.

Ni, Y. H. & Chen, D. S. (2010). Hepatitis B vaccination in children: the Taiwan experience. Pathologie Biologie, 58(4), 296-300. http://www.ncbi.nlm.nih.gov/pubmed/20116181.

Park, N. H., Chung, Y. H., & Lee, H. S. (2010). Impacts of vaccination on hepatitis B viral infections in Korea over a 25-year period. Intervirology, 52(1), 20-28. http://www.ncbi.nlm.nih.gov/pubmed/20068337.

Tajiri H, Tanaka H, Brooks S & Takano T. (2011). Reduction of hepatocellular carcinoma in childhood after introduction of selective vaccination against hepatitis B virus for infants born to HBV carrier mothers. Cancer Causes & Control, 22(3), 523-7. http://www.ncbi.nlm.nih.gov/pubmed/21191808.

Viviani, S., Carrieri, P., Bah, E., Hall, A. J., Kirk, G. D., Mendy, M. et al. (2008) Gambia Hepatitis Intervention Study.20 years into the Gambia Hepatitis Intervention Study: assessment of initial hypotheses and prospects for evaluation of protective effectiveness against liver cancer. Cancer Epidemi0ology, Biomarkers & Prevention, 17(11), 3216-3223. http://cebp.aacrjournals.org/content/17/11/3216.long.

Wasley, A., Kruszon-Moran, D., Kuhnert, W., Simard, E. P., Finelli, L., & Bell, B. (2010). The prevalence of hepatitis B virus infection in the United States in the era of vaccination. Journal of Infectious Diseases, 202(2),192-201. http://jid.oxfordjournals.org/content/202/2/192.long.

Wichajarn, K., Kosalaraksa, P., & Wiangnon, S. (2008). Incidence of hepatocellular carcinoma in children in Khon Kaen before and after national hepatitis B vaccine program. Asian Pacific Journal of Cancer Prevention, 9(3), 507-509 http://www.apocp.org/cancer_download/Volume9_No3/507%20Wichajarn%20.pdf.