Direct fluorescent antibody (DFA) of Yersinia pestis (Source: CDC)
Its pretty amazing that we still don’t have a vaccine against the plague. Work still goes on and it hasn’t been easy by any means, but it really isn’t a priority that you hear about much. Vaccines developed to date have issues with side effects and the need for repeat immunizations to be protective against pneumonic plague. The live, attenuated (weakened) Yersinia pestis vaccine, EV76, used in China today produces an immunity that lasts only 6 to 12 months. Not an ideal vaccine but it should produce a temporary ring of herd immunity around an outbreak.
Vaccine research is still answering some pretty basic questions like what is the nature of long-term immunity to Yersinia pestis? This is the question a Chinese group led by Ruifu Yang and Zhizhong Song are seeking to answer (Li et al, 2012). Plague is frequent enough in China for them to be able to assemble a cadre of long-term plague survivors to study their adaptive immunity.
Successful immunity to Yersinia pestis requires both a good humoral (antibody) and cellular (T cell) responses. Li et al (2012) gathered 65 plague survivors from the Yunnan-Guangxi-Fujian endemic plague foci who contracted the infection from 1990 to 2005, of which 23 were over 10 years post-infection. (Serum was collected in 2006.) They collected an additional 48 serum samples from people from the same endemic region of China who had never had a Yersinia pestis infection, and an additional 43 serum samples from people outside of the Y. pestis endemic area without a history of plague to serve as controls. They assayed their antibody response by ELISA and protein microarray and looked at their memory T lymphocyte response to the F1 antigen and LcrV protein.
Their results shed some light on our response to the plague. Of the 65 plague survivors, 78.5% (51/65) still produced a strong antibody response to the F1 antigen; the response rate for those whose infection was within five years was 88% and only decreased to 69.5% in patients infected over a decade earlier. Twelve of the thirteen longest survivors infected in 1990 were still reactive to the F1 antigen. They did not find a statistically significant difference between genders and there does not appear to be a difference based on age. The youngest age at infection was only three years old in 1997 and still produced a response in 2005. More importantly the antibody titer in 2005 correlated very well with their antibody titer at the time of infection.
The F1 protein is not the only antigen we make a response against in an active infection. They pooled serum for each year of infection for protein microarray testing. They found antibodies to LcrV and YopD in most survivors but the other proteins varied by year of infection (and therefore probably strain of the outbreak). These proteins are potential targets for new vaccines and for detection of F1-negative strains.
They assayed the interferon-gamma production of memory T cells by challenge with F1 antigen and LcrV in 7 plague survivors (infected 4-7 years previously) and 4 controls from non-endemic areas. The interferon-gamma levels produced by survivors and controls was not significantly different. Because Yersinia pestis is an intracellular pathogen early in the infection, the macrophage activation of interferon-gamma should play an important role in the early immune response to plague. Li et al (2012) discuss some possibilities for why they could not detect a difference in interferon-gamma, eventually concluding that the F1 antigen and LcrV proteins are probably not the dominant T cell antigens.
This study provides useful and interesting data for future vaccine development. Li et al (2012) conclude that this study is proof that the best route to an improved vaccine in the near future is an improved live, attenuated vaccine. The F1 antigen and the LcrV protein, the focus of current vaccine efforts, do not appear to be efficient at generating a good cellular immune response necessary to respond to pneumonic plague. With today’s biosecurity concerns, protecting against a bioterrorism event with aerosolized Y. pestis causing pneumonic plague must be the target of vaccine research.
For the historic plagues, this study illustrates that the immune response can last at least a decade or more. We should presume that the patients in this study were treated with antibiotics and possibly a passive vaccine (antibodies) so that their infection may have been milder and shorter than an untreated historic infection. The longer and more intense the infection, the better the protective immune response should be in survivors. Enduring active immunity could explain lowered mortality rates or altered demographics in successive waves of plague when they occur 10-20 years apart.
Li B, Du C, Zhou L, Bi Y, Wang X, Wen L, Guo Z, Song Z, & Yang R (2012). Humoral and Cellular Immune Responses to Yersinia pestis Infection in Long-Term Recovered Plague Patients. Clinical and vaccine immunology : CVI, 19 (2), 228-34 PMID: 22190397
Filed under: biosecurity, China, immunology, microbiology, Plague, public health, vaccines
