Was a vaccine against SARS-CoV-2 with durable immunity wishful thinking? 

Last fall in an email to a friend, after COVID cycled through vaccinated, boosted, and sometimes boosted again friends and family, I wondered whether a classic vaccine of attenuated or inactivated virus would have been a better choice to provide long-term immunity against SARS-CoV-2.

Then I wrote, “Not sure, as enough people have had the disease more than once. Maybe that should be our answer.” 

Lightbulb moment. Reinfection may be a sign there was no hope from the start for long-term immunity against COVID, no matter how clever modern technology is. 

It took me a couple of years to come to that conclusion. But the facts were out there before it all began. A physician in private practice even said to me at the beginning of the pandemic, “SARS-CoV-2 is the type of virus that’s difficult to get a vaccine for.” 

I didn’t want to believe the physician. Or maybe we were talking about different ideas at the time. Me, the vaccine technology and him, the biology of coronaviruses. I was enamored of the mRNA technology, able to deliver a vaccine designed in a weekend. Years had already been shaved off the process because of genomic sequencing. With Amazon Prime-like delivery, Chinese scientists fished SARS-CoV-2 out of the million bits of data generated from the genetic material captured in fluid from the lungs of stricken patients. 

Several decades of research were also behind the mRNA vaccine technology, which has been in use over the last ten years to treat cancer patients. They are a miracle therapy for some. People with terminal disease are still living today because of personalized mRNA vaccines. 

So I considered the major limiting factors for the vaccines to be whether the Spike protein would be toxic and whether the non-specificity of the liposome nanoparticles would end up delivering the recipe for the Spike protein into undesired places. 

The clinical trial moved out into the world, and SARS-CoV-2 vaccines soon fell into that category of vaccines preventing severe disease or hospitalization but not infection or transmission. People began to and continue to complain that none of the SARS-CoV-2 vaccines are vaccines. A recent joke was that to prove you’ve been vaccinated you need proof of infection. But they are vaccines. They cause an immune response – antibodies against the Spike protein are detected in the blood of vaccinated (and recovered) people. And cells that make these antibodies can be isolated from their blood. These cells are proof of exposure to the viral protein (or virus) and that it’s baked into the immune system.

The messaging of the SARS-CoV-2 vaccines got hijacked for whatever purpose. The companies involved never advertised the vaccines as preventing SARS-CoV-2 transmission or infection. The length of the clinical trials was not long enough to test for durable immunity. The results of the study demonstrated that proportionally, more cases of COVID and more severe cases occurred over the time interval examined in unvaccinated individuals. 

By the time the vaccine was available for the general population, the virus was onto different versions of itself. The data from the clinical trial was based on a previous virus, one that was less transmissible than by the time the vaccine was available to the rest of us less than a year and a half into the pandemic. 

The problem with the vaccine is it doesn’t work the way people want it to work. Vaccines are mimics. They engage our natural immune responses to mobilize a defense against specific foreign pathogens without the consequences of a real infection. The body has two major mechanisms of defense, and an army of cells is indoctrinated to do these jobs. Cells for an immediate response, known as the innate immune response, show up first due to the recognition of some common, primitive features among pathogens. A successful innate immune response sets in motion the second wave of response, the adaptive immune response, which generates antibodies and long-term immunity.

Viruses are not independent living organisms, just a sack of carbohydrates and proteins wrapped around a nucleic acid. They need the machinery in living cells to make copies of their genetic material and to spread. They must circulate among us to keep going. To optimize their survival, viruses have evolved ways to momentarily escape immune response. SARS-CoV-2 evades the immune defense by delaying the antibody producing process.

SARS-CoV-2 is a respiratory virus and enters the body through the cells lining areas, including the mouth, nose, and throat, known as the respiratory mucosa. SARS-CoV-2 is a “get in and get out” kind of virus. This virus sets up shop predominately in the cells where it enters and spreads to the next victim before the immune system has time to generate antibodies. The virus has moved on before you even know you’re sick.

The first problem with the SARS-CoV-2 vaccines is that the vaccine is delivered systemically, not where the virus enters the body. One of the differences between vaccinated and recovered persons is that while antibodies are detected in the blood of both, only recovered individuals develop a robust immune response in the respiratory mucosa. Having a first line of defense in the nose and throat may at least attenuate the disease in a second round, or fight it off before infection can take command.

The growing list of variants illustrates another characteristic preventing long-term immunity to SARS-CoV-2, the instability of the viral genome. The genome of SARS-CoV-2 is RNA. The copying of the RNA is not perfect. It’s prone to errors, and possibly designed to be so. While many of the error-filled genomes might be dead ends, once in a while an error (mutation) occurs that gives the virus an advantage over a previous version of the virus. 

When the virus jumps from one species to another, as from bats to humans, is the time when the copying of the genome is the most chaotic. The jump requires interaction with human proteins so the virus doesn’t quite fit – not yet. The mutations that stick are the ones that adapt the virus to the tools available in human cells. No matter how fast the mRNA vaccines can be put together, the sequence in them always lags behind the predominating variants. 

The vaccine may also not target the protein that will best disrupt progression of the infection. Although blocking the interaction at the receptor protein on human cells is a good strategy, a different protein might be more effective at interrupting infection. 

Finally, single proteins as the basis for durable immunity have not worked in the development of vaccines for other diseases, such as influenza and HIV. On this point, I found it confusing as to why natural immunity in recovered individuals was not regarded more highly. There’s the possibility of generating antibodies against a broader spectrum of proteins, and therefore, a better chance to fight off the virus and subsequent variants or other related viruses.

Until more is understood about coronaviruses and the immune system, scientists are looking into improving vaccine efficacy based on current knowledge and technology. The old-fashioned attenuated or inactivated virus was the basis for the Chinese vaccine. Some data from Hong Kong indicates that the efficacy after three doses is high (98%) in preventing severe disease in people over the age of 60. It’s often the case that a therapeutic works for some and not for others, and it’s only discovered when the data is broken down based on some criterium, such as age or sex or genetics. Younger people may have a more robust natural response that a vaccine can’t improve upon, unless it would prevent infection altogether.

The problem with this approach is that these vaccines take more time to develop and are more costly. And it’s more difficult to keep up with the latest variant. But attenuated virus challenges your immune system with the full array of viral proteins, as if you’ve gotten COVID but without getting sick. 

Some investigators have high hopes for vaccinating the respiratory mucosa through inhalation of nasal vaccines, but issues such as toxicity and the effects of repeated administration of the vaccine remain unknown. This approach may still require a combination of delivery methods. Systemic vaccination improves the development of Spike-specific immune cells in the respiratory mucosa with nasal vaccination.

My epiphany about SARS-CoV-2 and the vaccines came to me after a year and a half of watching friends and family cycle through vaccines and illness. I might have understood more, sooner, if I had taken the words of my physician friend seriously. In the end, I would discover the studies on coronavirus and immunity had been done, sometimes decades ago. 

But when I read the following sentence in a paper written by none other than Anthony S. Fauci, and published just 23 days after he retired from his position as head of the NIAID, I felt duped. 

“Because these viruses generally do not elicit complete and durable protective immunity by themselves, they have not to date been effectively controlled by licensed or experimental vaccines.” 

I’m glad Fauci is finally back to being a scientist. But now I wonder about the motivation behind his narrowly focused public health policy, vaccines for all from birth on up, while undermining natural immunity (in recovered persons) and therapeutics. The most noble of his motivations might have been to reach zero COVID. But the statement from the paper suggests he probably knew zero COVID could never be achieved. And that durable immunity was wishful thinking. 

The overriding sin is not about the vaccine – studies do show they help especially older or at-risk people – it’s that these scientists never spoke out against the institution of policies that took people’s jobs from them or kept children out of school, all the while fearing what they knew might be true about SARS-CoV-2 and immunity. While I do recall hearing some in our leadership and media claim that you will not get COVID if you take the vaccine, I do not recall anyone in power or in the media presenting a more realistic vision of what the vaccine could do for us, that is not until people began to realize it on their own. 

Now they know. Yes, it’s typical for a coronavirus.

I’m embarrassed as a scientist, that my community was not more supportive of open discussion. That the ones with the loudest voices criticized or canceled their peers deviating from focused narratives around SARS-CoV-2. And that more scientists did not translate journal articles into digestible information for more people. Or if they did, that it might not have been published.

The scientists at the lab bench did their job. They had prepared for such a moment over decades, and all their curiosities about weird phenomena across phyla fell together when the pandemic descended upon us. They pivoted overnight – their pipelines were set up to do it – and delivered vaccines, albeit imperfect, and therapeutics. 

But the scientific leadership failed in trusting the American people to make informed decisions. Even a two and a half year old can be convinced to do something she doesn’t want to do based on logic and knowledge. And a little respect.

©Janice Marie Nigro/janikiInk.com

Looking for a scientific editor or writer? Contact Janice Nigro at Janice Nigro Ink. I have published in Cell, Science, and Nature, and articles I have edited have appeared in Cancer Research, Clinical Cancer Research, PLoSONE, the Journal of Surgical Oncology, and Oncotarget.