First-generation vaccines are not the boosters you need
CLINICAL MATTERS
Dr. Edsel Maurice T. Salvana
As Delta variant wreaks havoc around the world, many people are starting to worry about their risk for infection and severe COVID-19. Vaccination is proceeding globally at an increasing pace. More and more breakthrough infections, however, are being reported, especially in countries with highly vaccinated populations. Breakthrough infections, or those infections that occur among partially or fully vaccinated people, have become more common. This is not only due to the fact that more people have been vaccinated, but also the apparent decreased efficacy of vaccines against infection with the Delta variant. With increasing breakthrough infections, the discussion inevitably turns to boosters.
How vaccines work
COVID-19 vaccines can protect people in three different ways, namely against severe disease, clinical disease, or establishment of infection.
The most important property of any vaccine is its ability to reduce the risk of severe or critical illness. The probability of dying from the infection goes down substantially. This protection is mediated by both neutralizing antibodies and cell-mediated immunity. Infection with COVID-19 is still possible, but symptoms will most likely be mild.
The immune response induced by the vaccine may also decrease the risk of developing symptoms of COVID-19. These symptoms include cough, colds, or fever. Not all vaccines, however, are able to fully protect against clinical disease, or some may only provide partial protection. Infection with COVID-19 is still possible but will most likely be asymptomatic or very mild. This protection can be mediated by both neutralizing antibodies and cell-mediated immunity. Vaccines that protect against clinical disease also protect against severe disease.
Some vaccines may also prevent establishment of any infection, whether asymptomatic, symptomatic, or severe and therefore block transmission. These are the hardest kinds of vaccines to make since it entails inducing a strong and lasting immune response. Proving transmission-blocking potential entails periodically testing asymptomatic vaccine recipients. This is laborious and expensive. Protection from any infection is usually dependent on the maintenance of significant titers of highly effective neutralizing antibodies.
With the rise of the variants of concern showing significant mutations in the spike protein, the initial high efficacy of vaccines against asymptomatic disease has substantially decreased. Initial data from Israel showed that protection from clinical disease for the Pfizer vaccine went down to as low as 30 to 40 percent against Delta from the previous 90 to 95 percent pre-Delta. More protection against severe disease, however, remains high. Delta is associated with very high viral loads, and the number of antibodies needed to neutralize these large amounts of virus is unlikely to provide enough protection from asymptomatic or clinical infection. In addition, the mutations in the spike protein of Delta make the antibodies generated by first generation vaccines less effective.
Waning immunity versus vaccine resistance
One major question that needs to be answered is whether the observed decrease in clinical efficacy of vaccines is due to waning immunity over time, or from decreased efficacy against the more vaccine-resistant variants such as Delta.
One surrogate test for protection afforded by vaccines looks for neutralizing antibodies, or antibodies against the spike protein. This is an imperfect surrogate as it does not capture two essential parts of the long-term response: the memory B-cells and the memory T-cells. Antibody levels in people without continuing exposure to the offending pathogen naturally decline, since it is not efficient for the body to continue producing high levels of antibodies that end up going to waste. Neutralizing antibody activity is a useful surrogate for determining the initial reaction to vaccination but is less useful for determining the longevity of the immune response. Moreover, some vaccines generate modest levels of neutralizing antibodies but mount robust cell-mediated T-cell responses which persist for a long time. Finally, the generation of memory B-cells allows the body to ramp up neutralizing antibody titers very quickly when there is re-exposure to the pathogen.
The observed decline in neutralizing antibodies for all current vaccines is expected. For the vaccines that elicit robust antibody levels such as mRNA vaccines (Pfizer, Moderna), it can take a while for these to decrease. For the vaccines that induce a variety of immune responses plus a modest amount of antibody production such as inactivated vaccines (Sinovac, Sinopharm), it is expected to be shorter. This does not mean the protection is gone, especially if memory B-cells have been generated. We do not know at what level of antibody the vaccines will stop protecting someone, and whether detectable antibody is even necessary to protect against clinical disease.
Distinguishing whether waning immunity or vaccine-resistant virus is responsible for the decrease in clinical efficacy has major implications on the need for a vaccine booster. If it is indeed due to waning immunity, then a booster may increase protection against clinical disease. If it is due to the inherent vaccine resistance of the virus, then a booster will have minimal effect since the antibodies generated, even at higher levels, will remain largely ineffective against the newer variants.
The current evidence suggests that it is not waning immunity that is responsible for the decreased efficacy of vaccines. Rather it seems that the newer variants, particularly Delta, are less likely to be stopped by the current first-generation vaccines, at least from a transmission and clinical disease standpoint. This is probably due to the less potent binding of antibodies induced by the original virus spike protein in the vaccine versus the spike protein of Delta. Severe disease effectiveness is preserved due to the presence of T-cell responses.
Giving a booster dose using the same old virus vaccine is unlikely to add much significant protection against clinical disease. Protection against clinical disease has substantially gone down even with very potent mRNA vaccines such as Pfizer. Boosters will also not add much to already robust T-cell responses that continue to protect against severe COVID-19 and are less dependent on antibody levels.
There is a subset of patients who may benefit from a third dose of a first-generation vaccine. These are patients who are immunocompromised, such as organ transplant patients or those undergoing chemotherapy. The US FDA has already approved third doses for this population. This isn’t a booster, but a third dose of primary vaccination for those who may not respond to the first two doses due to their impaired immunity. A third dose in these patients will increase protection against severe disease but will also not likely add much to clinical protection or transmission blocking potential.
Reformulated vaccines against Delta and other variants of concern
The best way to increase protection against variants of concern is to use vaccines that have been reformulated against the spike protein of these variants of concern. These will increase protection against clinical disease and potentially block transmission. This can be accomplished by using different variant types mixed together, the same way there are 23 serotypes in a Streptococcus pneumonia polysaccharide vaccine.
These reformulated vaccines are already in clinical trials for the different brands and are expected to be rolled out in the next few months. Instead of a booster using the old vaccine, these may be the best suited for improving protection, especially for highly exposed populations like healthcare workers and economic frontliners. There are also newer vaccines in the pipeline that are already being tweaked against the variants of concern. New vaccine platforms in development, such as live-attenuated virus and virus-like particles, are expected to closely mimic natural infection, which may afford stronger and longer lasting protection.
In the meantime, protection against severe disease is assured for most vaccinated individuals. Continuing to use masks and face shields and following public health standards will help keep case numbers manageable and preserve the healthcare system. This will enable us to live with COVID-19 while waiting for the new and better set of vaccines.