Reusing old vaccines to boost innate immunity against COVID-19

By Jocelyn Solis-MoreiraMay 31 2021

The COVID-19 vaccine is currently the best form of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. But a new perspective article published in the journal PNAS suggests it’s not the panacea to stopping SARS-CoV-2. Robert C. Gallo of the University of Maryland School of Medicine and colleagues of the Global Virus Network propose administering vaccines such as tuberculosis, measles, and polio that use already weakened viruses to boost innate immunity.

Ending the pandemic requires global vaccination, but some countries cannot accelerate vaccination campaigns like some Western countries. Some countries will be starting vaccinations in 2022 — leaving them at risk for developing more deadly and potentially immune-evasive variants.

By strengthening the body’s first line of defense, the researchers argue it will be beneficial for stopping new pathogens before it has time to spread. Older vaccines that stimulate innate immunity could stall viral spread and allow scientists more time to develop specific vaccines — potentially preventing another pandemic.

“The broad protection induced by LAVs would not be compromised by potential antigenic drift (immune escape) that can render viruses resistant to specific vaccines. LAVs might offer an essential tool to “bend the pandemic curve,” averting the exhaustion of public health resources and preventing needless deaths and may also have therapeutic benefits if used for postexposure prophylaxis of disease.”

Argument for strengthening innate immunity

Innate immunity is the body’s immediate reaction to an outside pathogen. Unlike adaptive immunity that takes days and hours to develop T cells and antibodies, innate immunity takes a matter of minutes. Previous work shows innate immunity alone was sufficient for overcoming pathogen and infections.

This figure illustrates how a healthy innate immune system protects most people within the population against infections. With an already robust or trained innate immune system, the overwhelming majority of people infected with a new pathogen, such as SARS-CoV-2, are able to eradicate the infection early during the asymptomatic or mildly symptomatic phase of infection. Without prior exposure or vaccination (e.g., with a messenger RNA vaccine), adaptive immunity takes days to weeks to kick in and is often suppressed in severe cases, contributing to a self-perpetuating and injurious hyperinflammatory response. The innate immune system often loses potency with age, certain comorbidities, immunosuppression, and with genetic susceptibility.

Innate immunity lies in its broad, nonspecific activation and the ability to inhibit multiple pathogens. With SARS-CoV-2, innate immunity is triggered by detecting the nucleotide sequence of the virus’s RNA.

The researchers note that vaccine-induced innate immunity from flu and HIV vaccines can last as long as adaptive immunity. Innate immunity also has innate memory to train the immune system to recognize a foreign pathogen sooner.

“In this article, we propose that during a pandemic (or epidemic), medical science could rapidly harness the power of innate immunity to induce partial protection against new (such as SARS-CoV-2) or reemerging pathogen threats and suggest that this might be achieved through the repurposing of some established live attenuated vaccines (LAVs), which are powerful inducers of innate immunity.”

The researchers note that innate immunity can control SARS-CoV-2 based on its success in preventing other coronaviruses such as SARS and MERS and may correlate with better clinical responses.

Coronaviruses derived from bats have also been associated with “an appropriate balancing of innate immune responses between resistance and tolerance.” Bats have high NK cells and IFN expression, suggesting innate immunity is needed to control SARS-CoV-2.

Older vaccines show partial benefit against COVID-19

Hoarding COVID-19 vaccines and mistrust against the rapid vaccine development has been a significant obstacle towards herd immunity. Using older vaccines — that have been trusted for years and widely accessible — could circumvent these issues.

Older live-attenuated vaccines also help because they target the specific virus of interest and provide a broad range of protection against other pathogens. Research from the past decade shows these vaccine’s nonspecific effects increase with booster shots. For instance, some animal studies showed the influenza H3N2 vaccine also protected against the respiratory syncytial viruses by increasing cytokine levels and leukocytes.

The epigenetic mechanism induced by LAVs in innate immune cells and their precursors: methylation and acetylation of histones after vaccination “mark” the gene necessary for host defense, leading to long-term changes in chromatin architecture leading to stronger expression upon subsequent stimuli.

Greater protection against SARS-CoV-2 was observed among healthcare workers who had a history of bacillus Calmette–Guerin vaccination. Separate studies confirmed these findings by observing fewer COVID-19 symptoms or less severe illness in people with the bacillus Calmette–Guerin vaccine.

There is an economic benefit to using older vaccines to stimulate innate immunity. Some of the available COVID-19 vaccines incur high costs for refrigeration and implementation. It would also be more cost-effective and protective to deliver live-attenuated vaccines as a booster for added protection instead of waiting four weeks for the second dose.

“Even a LAV with only 50% efficacy could then prevent several more primary infections per 1,000 vaccinees than would a vaccination schedule offering only a COVID-19 vaccine. With a Reff of 2, the total number of infections prevented could be twice the number of primary infections prevented. And even after 4 to 5 wk, the LAV could plausibly add effectiveness to the COVID-19 vaccine alone.”