Blocking inflammation to improve the effect of vaccines

UCL-led research team has found that an anti-inflammatory pill could make vaccines more effective for elderly people. An excessive inflammation reaction in older people can obstruct the immune system. The immune system declines with age, and people can be affected by pathogens they were once immune to, when it comes to cutaneous immunity - specific to skin - the immune system was being obstructed by skin cells that were too prone to producing inflammation responses.

To investigate immune responses, the researchers injected an antigen - a derivative of a pathogen that creates an immune response without inducing illness - into the skin of 175 participants (78 were over 65 years old and the rest were under 40). The pathogen was the varicella zoster virus (VZV), which causes chicken pox. After a person contracts chicken pox, they become immune to VZV, but it can re-activate in old age and cause shingles if T cell immune responses aren't strong enough.

All study participants had previously had chicken pox, meaning they should be immune. The researchers found that the older subjects exhibited weaker immune responses, as there was less T cell activation, and less reddening and swelling of the skin. The reduced response was not due to a lack of resident memory T cells present in the skin. As a control, they also injected a benign saline solution into the other arm of each participant.

 The researchers noticed that even the saline solution brought about an inflammation response in some of the older participants. Those who had the strongest inflammation responses to the saline solution had the weakest immune responses to the VZV, suggesting that the excessive inflammation was inhibiting VZV-specific immunity. Normally inflammation is a healthy part of the body's immune response, too much inflammation was getting in the way of the rest of the body's defences.

By analysing skin biopsies post-injection, the researchers found that the excessive inflammation was associated with activation of the p38 MAP kinase pathway. To test whether this enzyme was to blame, they conducted a follow-up test with 18 of the over-65 participants, who took Losmapimod, a drug that inhibits the enzyme in order to reduce acute inflammation responses. While the drug was designed for long-term use and has been trialled for treatments of COPD and arthritis, the participants only took the pill for 4 days, before once again being injected with the VZV antigen. Losmapimod treatment successfully increased the immune responses to the VZV antigen.
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Dengue immunity can protect against Zika

Manifestations of Zika virus (ZIKV) infection differ drastically. Sometimes they are catastrophic, most notably when they cause microcephaly in some babies born to infected mothers. At other times, they are mild and fleeting, suggesting that unknown factors temper Zika infections' severity.

Recently, dengue virus emerged as a prime suspect because it shares many genetic and structural characteristics with ZIKV and is endemic in most of the regions affected by Zika's global spread.
Mice rendered immune to dengue show "cross-protection" from subsequent Zika infection and then identifies specific types of immune T-cells capable of defending against both viruses.

These revelations have profound implications for efforts to build a potent anti-Zika vaccine. In some parts of the world Zika is almost like a secondary infection. It has spread into Brazil/Latin America and is moving into places in Asia where people previously had dengue. Vaccines targeting either virus could be engineered to induce both T cell and antibody responses effective to protect people in these areas.

When one encounters a pathogen in real life, two arms of the immune system spring into action to neutralize it. In the so-called humoral response, B-cells begin to secrete specific antibody proteins, which latch onto and neutralize pathogens in tissue or blood. Simultaneously, a cell-mediated immunity system also becomes active, deploying cytotoxic T-cells to directly recognize and kill pathogen-infected cells.

The ideal vaccine might mimic both antibody and T cell responses to block an infectious disease. But in truth, most (26 of 28 vaccines currently licensed for human use) stimulate primarily a B-cell or antibody response, which in many cases is sufficient. Reseache team created the first "sequential" mouse model mimicking dengue-then-Zika infection. To do that, they infected mice genetically vulnerable to this family of viruses with dengue virus.

Those mice became sick, recovered from infection, and hence acquired immunity to dengue, presumably because viral infection had mobilized their immune B-cells, T-cells or both. The group then inoculated the same mice with ZIKV and waited to see if mice showed ZIKV symptoms. But overall, mice that had previously acquired dengue immunity showed protection against Zika, as evidenced by a reduced burden of ZIKV in blood and tissues, such as brain, liver or testis, compared to control mice not "pre-inoculated" against dengue.

These experiments suggest that the reason that some people infected with Zika do not come down with disease is due to prior exposure to dengue. This may explain why Zika is not passed to the unborn child of every pregnant woman in dengue-endemic countries exposed to virus. In a different experiment, the scientists isolated cytotoxic T cells from the blood of dengue-immune mice and infused them into normal mice, a procedure known as adoptive T-cell transfer.

 When infused mice were then infected with ZIKV, they also showed disease resistance, supporting the idea that the T-cell arm of the immune system can do the heavy lifting against ZIKV infection. A successful vaccine would need to include components to induce not only a B-cell response but also a T-cell response.
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Aging leads to an imbalance in gut bacteria

According to a new study in PLOS Pathogens, different changes to the microbial community of the stomach may be the reason why conditions are associated with different risk levels and types of gastric tumor. Autoimmune disease or infection with Helicobacter pylori bacteria can damage the stomach and reduce gastric acid secretion.

Despite their similar effects, each of these conditions is associated with higher risk of a different type of gastric tumor. Meanwhile, widely used medications known as proton pump inhibitors PPIs also reduce gastric acid secretion, but they do not increase cancer risk. Elderly people tend to have different gut bacteria profiles from younger people.

This new research suggests that this change in balance is linked to inflammaging, which is related to most late-onset diseases and disorders. Inflammaging is a catch-all term for the tendency of elderly people to have generalized inflammation. It is thought to be related to evolved changes that the immune system undergoes as a person gets older.

It isn’t clear whether aging causes inflammation or inflammation causes aging, but the two go hand-in-hand, and susceptibility to many diseases goes along with both of them. Researchers took samples from older mice – whose gut bacteria composition, like humans’, changes with age – and introduced them to the bodies of younger mice. After the procedure, the younger mice developed chronic inflammation, like the inflammaging that would normally have struck them later in life.

They also transplanted gut bacteria from one group of younger mice to another group of mice of around the same ages to see if the immune response was just to the introduction of foreign bacteria. The mice with transplanted gut bacteria from older ones developed inflammaging.

The differences in the responses suggested to the researchers that aging leads to an imbalance in gut bacteria, such that there are more ‘bad’ bacteria than good in the microbiome. The proliferation of the bad bacteria leaves the gut lining more permeable to toxins that can contaminate the bloodstream and lead to disorders like inflammatory bowel disease, obesity, diabetes, anxiety, autism and cancer.
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Human antibodies and Ebola viruses

After analyzing the blood of a survivor of the 2013-16 Ebola outbreak, a team of scientists has discovered the first natural human antibodies that can protect animals against all three major disease-causing ebola viruses.

Monoclonal antibodies, which bind to a specific pathogens and toxins, have emerged as one of the most promising treatments for Ebola patients.

Most antibody therapies target just one specific ebola virus. For example, the most advanced therapy -- ZMappTM, a cocktail of three monoclonal antibodies -- is specific for Ebola virus (formerly known as "Ebola Zaire"), but doesn't work against two related ebola viruses (Sudan virus and Bundibugyo virus) that have also caused major outbreaks.

It's impossible to predict which of these agents will cause the next epidemic, it would be ideal to develop a single therapy that could treat or prevent infection caused by any known ebola virus.

 Both antibodies were able to protect animals (mice and ferrets) that had been exposed to a lethal dose of the three major agents: Ebola virus, Bundibugyo virus and Sudan virus.

The researchers also discovered the human genes that are the likely source of the immune cells that produce the two antibodies. These findings can
speed up the development of vaccines to prevent ebola virus infection.