Vaccines, Variants, and a Herd (Immunity) of Tigers, Oh My!

After over a year of worldwide shutdown due to the COVID-19 pandemic, the end appears near. Over 1.2 billion doses of vaccine have been distributed worldwide, including over 250 million in the United States. The pandemic is nowhere near over, however, and it is likely that COVID will never actually disappear but instead become endemic, like the flu. There are currently three vaccines authorized for emergency use in the United States, with another widely used in Europe and currently under Food and Drug Administration (FDA) review. Despite the encouraging progress on vaccination, many public health officials are concerned that the global vaccination effort is in a tight race against the potentially dangerous evolution of the SARS-CoV2 virus that causes COVID-19. After all, with more infections comes more opportunity for viral mutations. This post will discuss the available COVID-19 vaccines, the emerging variants, and what we know about the sustainability of immunity.

 

Background

In order to appreciate the differences among vaccines, an understanding of the “central dogma” of molecular biology is necessary. The central dogma summarizes how genetic information becomes functional molecules that impart function to a cell. The centra dogma is as follows:

DNA -> RNA -> Protein

DNA is the genetic code of an organism – aside from random mutations, DNA is identical in every cell in your body, and contains every gene that every cell may ever need. What determines whether a particular cell is a skin cell or a liver cell or a heart cell, for example, is the “expression” of particular genes. Gene expression means the selective coding of particular DNA gene sequences as a template to create RNA in a process called transcription. This RNA, known as messenger RNA or mRNA, is then used as a template for a sequence of protein building blocks in a process known as translation. Completed proteins then carry out various functions that define the cell type. Figure 1 presents a diagram demonstrating this process. DNA is much more stable than RNA or proteins, which is why it serves as the permanent genetic template for every cellular function in your body. RNA and proteins can be easily degraded and therefore must be replenished to continue carrying out their functions.

Figure 1: The central dogma of molecular biology (Source: Khan Academy)

 

Traditional vaccines work by exposing the immune system either to the pathogen (disease-causing virus or bacteria) itself or a surface protein from the pathogen that can be recognized by the immune system to protect against the actual infectious agent. The surface protein or protein segment recognized by the immune system is called an antigen. The first two approved vaccines, by Pfizer-BioNTech and Moderna, utilize a new technology that relies on RNA instead of traditional methods. This RNA strand contains the cellular instructions for an antigen of SARS-CoV2, the spike protein, which helps the virus bind to cells. The other two broadly available vaccines are by AstraZeneca and Johnson & Johnson. These vaccines use a viral vector (adenovirus) containing DNA coding for the same spike protein (although the specific sequences may differ). The adenovirus (which is not able to replicate) then injects individual cells with this DNA. While use of viral vectors is also relatively new, unlike RNA vaccines they have been used for previous outbreaks such as Ebola. Essentially, all these vaccines work similarly by utilizing the molecular sequences that code for the protein antigen, differing primarily by whether they rely on the DNA or RNA step in the central dogma. All except Johnson & Johnson involve a 2-shot regime. As stated above, DNA is much more stable than RNA, which is why the two mRNA vaccines must be stored at freezing temperatures while the Johnson & Johnson vaccine can remain indefinitely in a refrigerator.

 

Safety

The timeline for development of these vaccines is faster than any previous vaccines in history. However that fact in no way diminishes the safety profile of the vaccines. All of the vaccines available in the USA have been rigorously tested through the same clinical trial process as any vaccine. For the three vaccines available in the USA, there have been very few reports of any serious reaction. Typical side effects include rashes, injection site soreness, and general flu-like symptoms for a day or two. All of these symptoms are consistent with strong activation of the immune system – an indication that the vaccine is working – and reactions are stronger after the second dose of the regimen. The only potential severe effect that has been observed in the RNA vaccines is anaphylaxis (severe allergic reaction), which has been observed in a minuscule 0.025% of cases (although this is 10x higher than the rate from the flu vaccine) and always presents immediately. For this reason, vaccine recipients are instructed to remain at the vaccination site for up to 15 minutes following the injection. (Despite a great overall safety profile however, potentially severe and atypical blood clots have been identified in a very small minority of individuals vaccinated with either the AstraZeneca or Johnson & Johnson adenovirus vaccines. See my previous post for more details on that phenomenon).

So if safety steps have not been skipped, then what allowed these vaccines to be developed so quickly? There are many reasons, highlighted below:

• Modern technology allows scientists to determine the sequence of a pathogen almost instantly, which allowed the antigen RNA sequence to be developed in only two days.
• Both the RNA and adenovirus vaccines are more efficient than traditional vaccines and are built upon decades of research
• There was essentially unlimited funding, with developers paid in advance to mitigate risk and ensure that they could work as fast as possible
• Typical bureaucracy such as study design approval was expedited from months to days
• Manufacturing processes and materials for the vaccines were in development in parallel with the clinical trials, allowing production of the approved vaccines to take place immediately upon FDA approval
• Some phases of the vaccine approval process took place simultaneously to expedite collection of data
• There were plenty of motivated citizens ready to sign up as trial participants
• With COVID-19 being so contagious and widespread, the clinical trials were able to gather a large sample size of cases very quickly
• While a less than 1-year turnaround for vaccine development did indeed smash records for vaccine development, recent vaccines for other diseases have also been developed much quicker than historical timelines. For example, it only took 7 months for a DNA-based Zika vaccine to enter clinical trials, and the Ebola vaccine only took 5 years in total compared to the typical 10-15 year timeline.

 

Vaccine Efficacy

In August 2020, Dr. Anthony Fauci pessimistically stated “We don’t know yet what the efficacy might be. We don’t know if it will be 50% or 60%. I’d like it to be 75% or more.” In support of this pessimism, the FDA announced that it would approve a vaccine even if it was only 50% effective. For comparison, while many childhood vaccines are close to 100% effective (effectiveness refers to real world results, efficacy refers to trial data), the annual flu vaccine is only 40-60% effective.  Almost miraculously, every vaccine that has been developed beats that mark, with all of them just about passing the upper 75% threshold as well. Table 1 presents the effectiveness of the four vaccines currently in use across the USA and most of Europe. 

Table 1. Comparison of vaccine efficacy/effectiveness across various metrics

Vaccine	Overall Efficacy (trial data)	Overall Effectiveness (real world)	Effectiveness against severe illness/death	Reduces transmission?
Pfizer	95%	Up to 90-91%	95-100%	Yes, likely ~75-90%
Moderna	94%	Up to 90%	100%	Yes, likely ~67-90%
Johnson & Johnson	66-72% (moderate to severe disease)	Not yet available	85-100%	Yes, limited data suggests ~65%
AstraZeneca	76%-82%	Up to 70%	100%	Yes, likely ~60-70%

Not shown in Table 1 is the latest vaccine headed for approval and widespread distribution by Novavax, a modern take on traditional protein-based vaccines using nanoparticles to deliver a spike protein subunit. The Novavax vaccine showed excellent efficacy in clinical trials, with 90% efficacy overall and 96% against the original (non-variant) strain.

These efficacy results are based on the relative percentage of assumed infections prevented by the vaccine. In other words, the percent effectiveness represents the percentage of cases among all participants that were in the placebo group. As Table 1 shows, there is no single measure of effectiveness, and different clinical trials used different metrics. Notably, those stats represent maximum efficacy, 14 days after the second dose or 28 days after the single-dose Johnson & Johnson vaccine. Researchers have recently been analyzing efficacy at various points after the initial dose. Perhaps somewhat surprisingly, effectiveness after several weeks (just before the second dose is due) is quite high in all three 2-dose vaccines, with estimates of over 80% in the two RNA vaccines and over 70% in AstraZeneca. Efficacy does drop greatly within only 1 or two weeks of the first dose however.

An additional important question is how long the vaccines will retain effectiveness. While it is clear that a second dose of at least some vaccines increases the strength of protection, a second dose may also extend the LENGTH of that protection. Some concerning early data on individuals previously infected with COVID suggested that antibody levels may drop off greatly after only 3 months, however two recent studies suggest that efficacy of the Pfizer and Moderna vaccines remain at essentially the same level after 6 months. While the world may require yearly booster shots containing updates for any common variants (see below), it is likely that immunity would be sustained in some form for at least a year.

 

Variants

Over the past few months, the big concern is now variants – mutant forms of the virus that appear to be more contagious and in some cases more dangerous. Even worse, there is evidence that vaccines are less effective against at least some of these variants. There are three primary variants of concern internationally, as presented in Table 2. Many additional variants are also being tracked and examined and may become a larger focus in the future. Many other variants have been discussed, both from different US states and other countries, however most of them are either a mix of or similar to the three below.

Table 2. The three most common variants and their effects

Variant name	Origin	Effect on Transmission	Effect on Severity	Reduction in Immune Response
B.1.1.7	United Kingdom	~50% increased	Likely increased	Minimal
B.1.3.5.1	South Africa	~50% increased	Unclear	Moderate
P.1	Japan/Brazil	Unclear	Unclear	Moderate

As shown above, each variant has a different range of concerns in terms of increased spread, increased incidence of hospitalizations or death, and reduced sensitivity to the vaccine. While the British variant B.1.1.7 is potentially the most dangerous variant, existing evidence shows that it does not diminish vaccine effectiveness. The South African variant is perhaps the most concerning with increased spread and reduced immune response, while the Japanese/Brazilian variant is the least studied of the three but also has indications of reduced immune response.

Figure 2 presents the current state of knowledge (as of late March) on the three approved vaccines plus some others that have been either approved internationally or are in development. 

Figure 2. Vaccine efficacy and relative immune responses to different COVID-19 variants (Source: New England Journal of Medicine, March 2021)

The 501Y.V.2 variant represents the B.1.3.5.1 South African strain. There is mixed news in the data, depending on the vaccine. Both Pfizer and Moderna showed several-fold reduction in in vitro (i.e. laboratory test) response, with the greatest reduction against the South Africa strain, but without any real-world data available at the time. Johnson & Johnson interestingly showed very similar real-world effectiveness in South Africa compared to US trials (with no lab study data available). AstraZeneca unfortunately proved to be essentially useless against the South Africa strain both in vitro and in the real world. 

Further evidence for “increased immune escape” of the South African strain comes from data on extracted antibodies from recovered COVID-19 patients and vaccinated individuals. In this study neutralizing antibodies (virus-inactivating) demonstrated significantly reduced activity against the South African but not British strain, although overall antibody binding did not show any difference among strains.

In contrast to all the concerning data about the variants, some outstanding data on Pfizer and Moderna vaccines was recently released. Both vaccines did not demonstrate any significant reduction in effectiveness six months after administration. More strikingly, it appears that the immune response to Pfizer is so strong that even with the several-fold reduction in neutralizing antibodies shown in Figure 2, the remaining levels should be more than sufficient for protection. A small clinical trial in South Africa indicated that this is indeed true, with a 100% real-world effictiveness rate in South Africa where the B.1.351 variant is prevalent! More recent studies demonstrated that Pfizer has no reduction in effectivenes efficacy against the British variant and remains up to 75% effective against the South African variant. It is reasonable to assume that the similarly-designed Moderna vaccine will also be quite effective against this variant, however real-world data is not yet available.

 

Herd Immunity and Final Thoughts

Herd immunity is the indirect immune protection of a population regardless of whether every individual is immune because the percentage of susceptible individuals is so low that the pathogen cannot maintain community spread. Both natural infection and vaccination can contribute to herd immunity. The threshold for herd immunity is dependent on how contagious the disease is (a factor known as R₀) and the susceptibility of the population. See Table 3 for herd immunity data from several common diseases. As you can see, the Herd Immunity Threshold (HIT) is directly related to R₀.

Table 3. R_o and HIT for common infectious diseases (Source: Wikipedia)

Disease	Transmission	R0	HIT
Measles	Airborne	12–18	92–95%
Pertussis	Airborne droplet	12–17[53]	92–94%
Diphtheria	Saliva	6–7	83–86%
Rubella	Airborne droplet
Smallpox		5–7	80–86%
Polio	Fecal-oral route
Mumps	Airborne droplet	4–7	75–86%
COVID-19 (COVID-19 pandemic)		2.5–4[54][55]	60–75%
SARS (2002–2004 SARS outbreak)		2–5[56]	50–80%
Ebola (Ebola virus epidemic in West Africa)	Bodily fluids	1.5–2.5[57]	33–60%
Influenza (influenza pandemics)	Airborne droplet	1.5–1.8[53]	33–44%

Calculating R_o for COVID-19 has been difficult, with many estimates ranging from 1.4 - 4.0 and some as high as 5.7. All else being equal, based on the above chart that would suggest an HIT anywhere between 33% and 80%. Dr. Anthony Fauci and other experts have adjusted their estimates for COVID-19 HIT over time, from 60-70% all the way up to 80% or above. These estimates have risen both due to concerns about more contagious variants and even some admitted attempts at playing sociologist in order to balance motivating the public to get vaccinated and keeping the goal within reach. The good news is that we now have real-world data from Israel, which has almost completely eliminated COVID-19 spread as it approaches 60% of the population being fully vaccinated. Every nation is different, with different social behaviors and public health practices. However when considering the consistent drop in cases over the past month as the USA has surpassed 30% fully vaccinated, the limited evidence suggests that herd immunity may be reached at a HIT of around 65%. Additionally, HIT is based on both vaccinations and natural immunity (although natural immunity is likely weaker). Therefore we may be closer to the HIT than it seems based merely on vaccinations alone.

As has been repeated ad nauseum in the media by public health leaders, all available vaccines are overall safe and effective. However, not all of the vaccines are the same. While the recommendation to simply get the first one available was worthwhile advice early on when supply was limited, most Americans are now fortunate enough to have options. Hopefully this post can aid in someone’s choice or increase their confidence in receiving a vaccine. The concern over variants also appears to be mostly overblown, at least for now, however new mutations arise continuously and without suppressing spread globally we cannot be sure that we won’t be at greater risk in the future. It is for this reason why a need for booster shots, perhaps annually, is fully expected.

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