In research published in Brain, Behaviour, and Immunity in July 2023, a group from Tel Aviv University found that there is a link between behavioural stress and the effectiveness of vaccines. Although acute stress in lab models 9-12 days after vaccination increased antibody responses to a vaccine by 70%, they noted that this was at a cost: reduced antibody breadth. This leads to “diminished” protection against variants. The study is the first to investigate the consequences of acute stress on a vaccine’s effectiveness.  

Vaccines under pressure 

Dr Natalia Freund, in whose lab the study was conducted, states that the hope was to understand the “correlation between stress and the body’s ability to develop an immune response following vaccination”.  

“The prevailing assumption is that the effectiveness of a vaccine is determined mainly by its own quality. However. Over the years, professional literature has reported influences of other factors as well, such as the age, genetics, and microbiome on the outcomes of vaccination”. 
What did they find? 

Dr Freund explains that acute stress has a “dramatic impact”. Acute stress is the mental state caused by (real or imagined) immediate threats; it involves the secretion of adrenaline and stimulation. The investigation involved vaccinating mice with two different vaccines: the model protein Ovalbumin and a fragment of the SARS-CoV-2 spike protein. 9 days later, as adaptive immunity activated and antibody production began, the mice were “subjected to a widely used behavioural paradigm simulating acute stress”.  

Two and a half weeks after this stress exposure (30 days after vaccination) the level of antibodies of the stress-experiencing mice was 70% higher compared to the control group. This was a surprise to the team, and was observed in animals vaccinated with either of the vaccines. However, the key finding is that the immune system of the stressed animals was not cross-reactive to variants of the protein used in the vaccine. This means that after stress, the immune system was directed solely towards the original vaccine, showing no response to slightly different proteins.  

For Dr Freund, this is a significant observation as “the purpose of vaccination is not only protection against a specific pathogen, but also creating a long-lasting immunological memory for protection against future mutations”.  

Challenging assumptions 

Dr Freund was “surprised” that the response to the vaccine was “more effective in animals that had experienced stress”, as she and her colleagues had “assumed just the opposite”! The enhanced antibody activity was mediated by the cellular receptor that identifies adrenaline, the beta2 adrenergic receptor.  

“When we blocked this receptor, either pharmacologically or by means of genetic engineering, the effects of stress were completely eliminated.” 

However, to the “great surprise” of the researchers, the “breadth” of the immune response was reduced by about 50% following stress. This is described as a “classical fight or flight response”, demonstrated at molecular level. When stressed, the immune system produces stronger, and more, antibodies, to address the immediate infection.  

“This large energetic investment in the here and now comes at the expense of future immunological memory.” 
What about humans? 

After investigating the effects of stress in mice, the team wanted to see if humans also display the “post-stress immune impairment”. Therefore, they cultured B cells taken from the blood of people who had been infected with COVID-19 in the “first wave”. Then, they induced stress in the cultures with an adrenaline-like substance. This stimulates the beta2 adrenergic receptor, identified in the earlier part of the study as a mediator of the response to stress. B cells express “a very high level of these receptors”, but it was previously “unclear” why they needed the ability to respond to adrenaline.  

“Just like in mice, human cells also exhibit a zero-sum game between the intensity and breadth of the immune response. When the adrenaline receptor is activated during stress, the entire immune system is stimulated, generating antibodies that are 100-fold stronger than antibodies produced in cells that had not undergone stress.” 

However, the “diversity” of antibodies was reduced by 20%-100%.  

“Stress 9 to 12 days after vaccination, at the time when B cells are generating high affinity antibodies, enhances short-term immunity and damages long-term memory.”  

This can be explained from an evolutionary perspective, suggests Dr Freund.  

“Stress can be caused by different factors. We tend to think of mental stress, but physical illness also causes a form of stress. When the body contracts a virus or bacteria it experiences stress, and signals to the immune system that the top priority is getting rid of the pathogen, while investing energy in immunological memory is a second priority.”  

What might this mean for vaccination programmes going forward? To read the paper click here, and don’t forget to subscribe for more like this.