Should vaccines be adjuvenated with alum?

For a long time vaccines were adjuvenated (made more effective) by adding aluminium salts to them.  Eventually, however, sufficient concerns about the practice emerged for the practice to be dropped and Covid vaccines did not contain such adjuvants.  

But was something lost by that?  Might the Covid vaccines have worked better with adjuvants?  The study below used mice to suggest an answer to that.  They found that  breakthrough infections were much worse with adjuvants.

While COVID-19 vaccines have generally remained effective in stopping more severe illness associated with SARS-CoV-2, the virus behind COVID-19, significant concerns emerge regarding vaccine-associated enhanced respiratory diseases (VAERD) post breakthrough infections. This means even though people get vaccinated, because the COVID-19 vaccines are not of the sterilizing type, they fail to protect against infection, especially over time, less intermittent boosters to bolster protection. Importantly, this recent animal study reveals spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections.

Other research such as a study funded by China’s Beijing Science and Technology Plan and Emergency Key Program of Guangzhou Laboratory, found that both novel low-dose and high-dose adjuvanted inactivated SARS-CoV-2 vaccine with CpG and Alum induced high levels of specific IgG antibodies as well as neutralizing antibodies against SARS-CoV-2, and the continuous stability of high-level neutralizing antibody titers over time demonstrates long-lasting immunity.

The prominent study team was represented by Weishan Huang, Ph.D. Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, as well as Cornell University’s Department of Microbiology and Immunology, College of Veterinary Medicine.

With a focus on virology and immunology, Huang’s lab studies the development and functions ­­of regulatory immunity and immune memory during vaccination, infections, and cancers.

With this infrastructure and expertise in place, plus support in the form of grants by the National Institutes of Health, and a “Big Idea Research Grant” from the Provost’s Fund at Louisiana State University, Huang and colleagues from Louisiana State University sought to gain a more comprehensive understanding of possible risks and the underlying mechanisms of VAERD designed a study involving the immunization of ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN.

After the immunization, the scientists challenged (intentionally infected) the mice with SARS-CoV-2 to establish the breakthrough condition.

What were the findings?

In this case, the authors report that their experimental vaccine A) elicited robust neutralizing antibody responses, B) reduced viral titers and C) enhanced host survival. Yet upon breakthrough infection, the vaccinated animals presented “severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines.”

Th2/Th17 cytokines are groups of signaling molecules produced by specific subsets of T-helped cells (Th cells) that play an important role in the immune system. These cytokines are involved in regulating responses and inflammation, and they are often associated with various immune reactions.

The study team conducted intracellular flow cytometric analysis (a technique used to identify cell types plus analyze signaling and functional responses within cell lines and heterogenous cell samples), revealing a systemic Th17 inflammatory response, especially intense in the subjects’ lungs.

The study authors report in the uploaded preprint server manuscript that the generated data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology post breakthrough infection.

Food for Thought

There are no easy vaccine fixes for SARS-CoV-2, the virus behind COVID-19. These authors reaffirm that especially important principle. They declare in this yet-to-be peer-reviewed paper, “In conclusion, this research underscores the complexity of COVID-19 vaccination and the need for a comprehensive understanding of vaccine-induced immune responses. While vaccines remain a vital tool in combating pandemics, the potential for VAERD highlights the importance of ongoing research, surveillance, and careful vaccine development to achieve broad protection and maximal safety.”

Next Steps

Do these findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19? Does the study output point to the necessity to enhance vaccine formulations for broad protection and maximum safety?  The study authors believe so.


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