Correlates of Protection

In search of a true Correlate of protection against new viruses.

The old world of immunology and vaccination are crumbling. For 100 years we thought that our antibody levels are synonymous with Protection against the microbe. Whenever the efficacy of a vaccine needed evaluation, we only measured the serum antibody level against the antigen at serial intervals and standardised an in vitro minimum inhibitory concentration MIC.

Often the licensing procedure of an immunising agent is identical with the procedure for an antibiotics: in vitro serology to standardise a neutralising titre. But the mode of action of an immunising agent is radically different from an antibiotic. Unlike an antibiotics that can be tested from the reduction of bacterial colony on a culture plate, Vaccines are different. They are biologics that recruit our own cells, train them and leave behind an immune memory. Unlike antibiotics, their efficacy can not be increased by increasing the strength of the inoculum.

Covid-19 changed all that. Now we know that presence of antibody against the coronavirus hardly correlates with protection against the disease. There were a lot of reports of reinfections ( after previous one) and breakthrough infections ( after full vaccination). Labs all over world simply failed to establish a universally acceptable MIC against the infection.

The titre of circulating antibody does not correlate with protection against the pandemic.

What are our knowledge about Immune responses to vaccines that correlate with protection ?

This concept got a radical change after the Covid-19 pandemic. Today we know that serum total antibody or specific IgG levels against the SARS COV 2 only indicates past exposure or vaccination status, not protection against disease.

Here’s is the thing:

Adaptive immunity takes 14 days to mount. But viruses like Influenza and Covid-19 take only 7 days to enter our cells and vanish before the antibodies can appear. Antibodies are not the primary protection against them. Innate immunity and Cellular immunity have variously been implicated. but still we don’t have universal agreement that should be followed world over.

I have put forwarded my ideas in the following few lines

1. all current vaccines work through antibodies in serum or on mucosa that blocks infection by preventing microbes from entering cells or neutralising them directly in blood. Till date, serum antibody titres (GMT) are still taken as the Correlates of Protection. All our literature on vaccine efficacy still stand on them.

Covid-19 pandemic has radically changed that concept. Antibody detected against the SARS COV-2 only indicates previous exposure to the virus or vaccination. It failed to correlate with the protection against the infection.

The age old concept of studying GMT of antibodies to measure the efficacy of an immunising agent is seriously re-looked into especially in short acting intracellular pathogens like Influenza and Corona virus.

2. Immune memory is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases.

3.  Cellular immunity acts to kill, clear or suppress intracellular pathogens and may also synergise with antibody. 

4. For some vaccines, we have no true correlates, but only useful surrogates, for an unknown protective response.

The generalisation that vaccine-induced antibodies prevent   entry of virus into a cell whereas cellular immune functions clear infection still holds true. But that simple distinction becomes blurred in many instances.

 Specific antibody and cellular responses are multiple and redundant, so that vaccines for some pathogens protect through more than one immune function. 

Although mucosal and cellular immune responses are clearly important to protection by some vaccines, most vaccines licensed today depend for their efficacy on serum antibodies. Particular levels of antibodies can be identified that confer protection most of the time.

A serious discussion to identify definite correlate protection ability of immunising agents is the need of time. It should be part of our licensing procedure at least for new generation of immunising agents.

Please think.

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