Last year will go down in history as one of the most volatile on record for the stock market. The uncertainty created by the coronavirus disease 2019 (COVID-19) pandemic caused the benchmark S&P 500 to lose over a third of its value in less than five weeks during the first quarter. The subsequent nine months brought a record-breaking rally that saw the S&P 500 end the year higher by a double-digit percentage.

Though volatility was present in all sectors and industries, it was particularly notable among healthcare stocks. While it's not uncommon for positive clinical data to send a biotech stock or medical device company soaring, it's very much out of the ordinary to see 1 in 5 healthcare stocks with a $300 million or larger market cap end the year higher by at least 100%. That's what happened in 2020.

Among the 126 healthcare stocks that at least doubled last year, three did so well that a $100,000 investment in them would have turned into well over $1 million.

A messy pile of one hundred dollar bills.

Image source: Getty Images.

Novavax: $2.99 million (+2,889%)

The top-performing healthcare in stock in 2020 was clinical-stage drug developer Novavax (NASDAQ:NVAX) -- and it wasn't even close. As of the Dec. 30 close, Novavax shares were up nearly 2,900%. Had you invested $100,000 when the year began, you'd pretty much be sitting on $3 million to end 2020.

As you might have guessed, the investor interest surrounding Novavax has to do with its work in developing a COVID-19 vaccine. In early stage trials, NVX-CoV2373 led to 100% of trial participants developing neutralizing antibodies after the second dose.

The only real issue for Novavax in 2020 is that its phase 3 trial in the U.S. was delayed. That allowed some of its peers to get ahead on producing and distributing their COVID-19 vaccine. The vaccines from Pfizer/BioNTech and Moderna were both granted emergency use authorization in mid-December. Meanwhile, Novavax only began its phase 3 trial for NVX-CoV2373 in the U.S. and Mexico a few days ago. An interim readout on vaccine efficacy is expected in the first quarter.

On the bright side, Novavax was able to kick off a late-stage study in the U.K., as well as a phase 2b trial in South Africa, which should both yield data early in the first quarter of 2021. Though this data won't sway the U.S. Food and Drug Administration, it could clue investors in to the vaccine's expected efficacy.

It's going to take multiple successful vaccines to end the coronavirus pandemic, so the opportunity is definitely there for Novavax to secure billions in annual sales with a successful late-stage study in 2021.

A lab technician using a pipette to place liquid samples under a microscope.

Image source: Getty Images.

Cardiff Oncology: $1.41 million (+1,311%)

Brace yourself: A healthcare stock skyrocketed in 2020 without having anything to do with the coronavirus disease. Clinical-stage cancer-drug developer Cardiff Oncology (NASDAQ:CRDF), which began the year as a micro cap, would have turned a $100,000 investment into more than $1.4 million.

The buzz surrounding Cardiff Oncology is all about its leading oral drug candidate, onvansertib. This is a treatment that targets the Polo-like kinase (PLK1) enzyme, which is overexpressed in select cancer types. Cardiff is studying onvansertib in three clinical indications, including two phase 2 trials that combine it with other approved treatments.

What really lit a fire under Cardiff's stock was a mid-September poster presentation at the European Society for Medical Oncology. This data revealed interim results for onvansertib in combination with FOLFIRI and Avastin as a treatment for KRAS-mutated metastatic colorectal cancer. The KRAS mutation occurs in about half of all colorectal cancer patients. Of the 11 evaluable patients, five achieved a partial response, eight had a durable response ranging between 5.5 months and 12 months, and only one patient's condition progressed while on the treatment in under six months.

This is a small subset of patients, and progression-free survival has yet to be determined. Still, this was impressive data from a clinical-stage company that previously hadn't made any waves. 

The good news for Cardiff Oncology investors is that 2021 promises to a busy year. As pointed out by my Foolish colleague Keith Speights, the company's phase 2 prostate cancer study and phase 1b/2 colorectal cancer study should be done by May 2021. Meanwhile, the company's acute myeloid leukemia phase 2 study will conclude later this year. We'll know soon enough if Cardiff's big gains in 2020 are merited.

Prescription tablets placed atop a one hundred dollar bill, with Ben Franklin's eyes peering between the tablets.

Image source: Getty Images.

Vaxart: $1.71 million (+1,606%)

Surprise! The third healthcare stock that would have turned $100,000 into well over $1 million is a company engaged in developing a COVID-19 treatment. Investors who gambled $100,000 on Vaxart (NASDAQ:VXRT) to begin the year are now sitting on north of $1.7 million.

The hype surrounding Vaxart's vaccine, VXA-CoV2-1, is twofold. First, it's an oral tablet, as opposed to a shot. Vaxart's drug could be the perfect solution for needle-phobic recipients if it's effective. 

Secondly, Vaxart's preclinical data involving hamsters appears to suggest that VXA-CoV2-1 provides superior protection relative to other vaccines currently in development. Specifically, Vaxart notes systemic and mucosal immunity from its oral treatment, as opposed to just systemic immunity provided by other vaccines.

Keep in mind that Vaxart has a ways to go on the clinical front. It only began dosing its first subject in an early stage trial in mid-October. A number of deep-pocketed drug developers are much further along in developing their COVID-19 inoculations. 

Furthermore, Vaxart is also contending with an investigation by the Securities and Exchange Commission concerning allegations that it misstated its involvement in Operation Warp Speed. Operation Warp Speed is a public-private partnership that's doled out billions of dollars to accelerate the development, manufacturing, and distribution of COVID-19 vaccines.

A tablet vaccine is an intriguing idea, but a lot will need to go right for Vaxart to maintain its mammoth 2020 gains.

This article represents the opinion of the writer, who may disagree with the “official” recommendation position of a Motley Fool premium advisory service. We’re motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.